1、Q2 2022www.deep-pharma.techinfodeep-pharma.techEpigenetic Drugs:From Cancer to AgingApproach of the Report3Executive Summary4Mindmap5Introduction to Epigenetics5Targets for EpiDrugs9Rise of EpiDrugs Development13Growth of Scientific Interest in EpiDrugs15Key Market Players17Selected Collaborations18

2、EpiDrugs Repurposing19Epigenetics and Cancer21Table of ContentsBiological Basis of Cancer22Epigenetics of Cancer24DNA Methylation in Cancer25Chromatin in Cancer28Combination Therapy in Cancer33Epigenetics and Aging40Aging Epigenome42Market Overview49Key Takeaways56Appendix:List of Entities57Disclaim

3、er70Deep Pharma Intelligence2Relying on various research methods and analytics techniques,the analysis provides a comprehensive overview of the Preclinical and Clinical Trials Industry.This approach has certain limitations,especially when using publicly available data sources and conducting secondar

4、y research.Deep Pis not responsible for the quality of the secondary data presented herein;however,we do our best to eliminate the said risks using different analytics techniques and cross-checking data.Please note that we did not deliberately exclude certain companies from our analysis.Nor was it d

5、ue to the data-filtering method used or difficulties encountered.The main reason for their non-inclusion was incomplete or missing information in the available sources.Approach of the ReportIndustry-Specialised Databases Data SourcesMedia Overview(Articles and Press Releases)Industry Reports and Rev

6、iewsPublicly Available Sources(Websites)DescriptiveAnalysisComparative AnalysisQualitative Data CollectionMixed Data ResearchData TriangulationData FilteringApplied Research and Analytics MethodsDatabase75Drugs80Companies85R&D CentresThe database was formed based on:the identification of companies t

7、hat conduct or have conducted clinical or preclinical research of drugs the identification of companies that research or develops biomarkersDeep Pharma Intelligence3Ever since being discovered,epigenetics which significantly influences gene expression,which means that to some extent,epigenetics is i

8、nvolved in almost all cellular processes have played a key role in our understanding of human biology.Because of their importance in cellular physiology,aberrant epigenetic regulations are associated with various human diseases,especially in different forms of malignancies.In addition,many studies h

9、ave shown that epigenetics plays a central role in ageing.The involvement of epigenetics in many essential cellular processes made enzymes that regulate epigenetic changes a potential target.Currently,more than 10 drugs targeting epigenetic regulators have been approved for treating different diseas

10、es,and more than 60 other epigenetic drugs are in clinical trials.These numbers will only grow through the years,making this research direction more and more promising.Currently,most of the epigenetic research is dedicated to cancer.However,in the last years,another prominent approach has appeared r

11、epurposing epigenetic drugs for other diseases,including age-related diseases.Main Features of the Analytical Case StudyDatabase of Key Market Players Role of Epigenetic in CancerRole of Epigenetic in Aging and Aging-Related DiseasesOverview of Clinical Trials for Epigenetics Drugs at All PhasesIn-d

12、epth Review of Epigenetic Drugs for CancerAssessment of Epigenetic Drugs and Biomarkers for AgingEpigenetic Clinical Trial Market Review and PredictionsDeep Pharma Intelligence4Executive SummaryCompanies in EpiDrugs Development Q2 2022 Companies-80DEEP PHARMA INTELLIGENCEEpigenetic Biomarkers for Ag

13、ingHDAC inhibitors DNMT inhibitors Other inhibitors Epigenetics is the study of how cells control gene activity without changing the DNA sequence.The word“epigenetic”literally means“in addition to changes in genetic sequence.”A vast range of diseases,behaviours,and other health markers,including mal

14、ignancies of practically all sorts,cognitive dysfunction,and respiratory,cardiovascular,reproductive,autoimmune,and neurobehavioral ailments,already have some degree of evidence relating them to epigenetic processes.Currently,there are known many epigenetic processes,including methylation,acetylatio

15、n,phosphorylation,ubiquitylation,and sumoylation.The best-known epigenetic process is DNA methylation.This is the addition or removal of a methyl group(CH3),predominantly where cytosine bases occur consecutively(CpG islands).Another significant epigenetic process is chromatin modification.Chromatin

16、is the complex of proteins(histones)and DNA that is tightly bundled to fit into the nucleus.The epigenome consists of chemical compounds that modify or mark the genome in a way that tells it what to do,where to do it,and when to do it.Introduction to EpigeneticsDeep Pharma Intelligence6Sources:Europ

17、ean Association for the Study of Diabetes,Environmental Health Perspectives,National Human Genome Research InstituteEpigeneticsDNA methylationHistone methylationHistone acetylationHistone phosphorylationHistone ubiquitylationOncologyNeurodegenerative Cardiovascular Cognitive Autoimmune Epigenetic Pr

18、ocesses:3 Classes of Epigenetic Regulation Deep Pharma Intelligence7DNA MethylationHistone ModificationsNon-coding RNA actionThe process of DNA methylation involves the addition of a methyl(-CH3)group to DNA.This group is added to specific locations on DNA(CpG islands),where it prevents proteins fro

19、m attaching to DNA and reading the gene.Demethylation is a method used to remove this chemical group.Methylation typically turns genes off,while demethylation turns them on.DNA wrapped around the proteins called histones.Proteins that read the gene cannot reach DNA wrapped tightly around histones.Th

20、e genes that are wrapped tightly around the histone are turned off,whereas others are turned on because they are loose around the histones and accessible to“readers”.Histones can have chemical groups added or deleted,affecting whether a gene is wrapped or unwrapped(on or off).DNA is guide with instr

21、uction for creating coding and non-coding RNA.Proteins are made with coding RNA.The non-coding RNA regulates gene expression by binding to coding RNA and breaking it down,preventing it from being used to generate proteins.Proteins may be recruited by non-coding RNA to alter histones and switch genes

22、 on or off.Sources:European Association for the Study of Diabetes,Environmental Health Perspectives,National Human Genome Research InstituteH3H4H2AH2BHistone OctamerAcMeDNAHistone TailAcetyl GroupMethyl GroupClosed heterochromatinGeneGeneOpen heterochromatinMethylatedUnmethylatedEpigenetic Activator

23、Epigenetic RepressorIncRNAIncRNATranscription RepressionTranscription ActivationOverview of the Epigenetic RegulationEnzymes that add histone modifications such as acetylases,methylases,kinasesEnzymes that remove histone modifications such as deacetylases,demethylasesProteins that bind to histone mo

24、difications and alter gene activity and protein productionDeep Pharma Intelligence8Sources:ReverselogixOur chromosomes are made up of DNA wrapped around proteins and packed together in a beautiful hierarchical arrangement,which we inherit from our parents.Individual DNA strands are wrapped around sp

25、ecialized proteins in tightly coiled chromatin fibers,which are made up of smaller units(nucleosomes)than contain histones.The tail of the histone protein,which protrudes from the nucleosome,can be marked.More than 800 epigenetic enzymes affect genome activity at numerous levels.Epigenetic modifiers

26、 fall into four categories:writers,who add specific marks to DNA or the core histones H2A,H2B,H3,and H4;readers,who detect these marks;and erasers,who remove them.Epigenetic drugs(EpiDrugs)now target proteins in these three groups.Inhibitors of DNA-modifying enzymes,such as DNA methyltransferases(DN

27、MTs),which can methylate specific cytosine or adenosine nucleotides in DNA,inhibitors of ten-eleven translocation(TET)enzymes that catalyse the oxidation of 5-methylcytosine and inhibitors of mutant versions of isocitrate dehydrogenase(IDH)enzymes,are among these epi-drugs.Other epi-drugs,such as hi

28、stone acetyltransferases(HATs),histone deacetylases(HDACs),histone methyltransferases(HMTs),and other protein arginine methyltransferases(PRMTs)and histone demethylases(HDMs),inhibit writers or erasers of histone arginine and/or lysine post-translational modifications(PTMs).Readers of histone PTMs,s

29、uch as bromodomain and extra-terminal domain(BET)family proteins(BRDs),which bind acetylated lysine residues in histones,are inhibited by another class of epi-drugs.Epi-drugs that target histone chaperones and chromatin remodeling factors are also being developed.Targets for EpiDrugsDeep Pharma Inte

30、lligence9Sources:Morel et al(2020).Nature Reviews Clinical OncologyClassification of Epigenetic InhibitorsDeep Pharma Intelligence10Designed by PoweredTemplatePA(M)HiPA(M)HiChromatin remodelers inhibitorsDNA methyltransferase inhibitorsHistone deacetylase inhibitorsHistone methyltransferase inhibito

31、rsHistone demethylase inhibitorsBromodomain inhibitorsTen-eleven translocation inhibitorsHistone acetyltransferase inhibitorsIsocitrate dehydrogenase inhibitors HDMiHATiIDHiBETiHMTiHDACiDNMTiTETiCRiEpigenetic InhibitorsDeep Pharma IntelligenceSources:Roberti et al(2019).Clinical EpigeneticsBy blocki

32、ng the activation of DNA methylation,DNMTi can repair the expression activity and function of tumour suppressor genes,consequently limiting tumor cell growth and triggering apoptosis.HDACi are emerging as promising anti-cancer medications that regulate epigenetic and non-epigenetic factors in altere

33、d cells,causing cell death,apoptosis,cell cycle arrest,cell mobility inhibition,and antiangiogenesis.To create a repressive chromatin environment,HDACs remove acetylation marks from histone tails.HDACi inhibits the activity of HDAC,which renew histone acetylation.Readers that identify acetylated lys

34、ine are bromodomain and extra-terminal motif(BET)proteins.BETi bind to the bromodomain of BET proteins in a reversible manner,disrupting crucial protein-histone interactions.BRD4,which is translocated in some malignancies,is required for the production of oncogenes like MYC,and one of the better-stu

35、died targets of BETi small molecules is the pro-inflammatory gene NFKB.Epigenetic Inhibitors:Examples of Mechanism of Action11DNMTiHDACiBETiOverview of Key DrugsDeep Pharma Intelligence12Sources:Citron,F.;Fabris,L.Targeting Epigenetic Dependencies in Solid Tumors:Evolutionary Landscape Beyond Germ L

36、ayers Origin.Cancers 2020DNA methylationHistone methylationHistone acetylationBET proteinsNucleosomeEpigenetic WritersEpigenetic ReadersEpigenetic ErasersDNMTis5-AzacytidineDecitabineGuadecitabineZebularineDNMTsBETisJQ1I-BET151GS-626510OTX015RO6870810KMTsEZH2isTazemetostatCPI-1205UNC1999GSK126EHMT2i

37、sBIX-01294HDACisVorinostatBelinostatPanobinostatRomidepsinEtinostatGivinostatHDACsKDMsTETsH2AH4H3H2BRise of EpiDrug DevelopmentDeep Pharma Intelligence13 Preclinical Phase I Phase II or III Approved13DNA MethyltransferasesIsocitrate Dehydrogenase 1 or 2Histone DeacetylasesHistone MethyltransferasesH

38、istone DemethylasesBromodomain proteinsChromatin remodelersCTCF binding proteinsHistone acetyltransferasesSources:Dan L.Longo(2020).The New England Journal of Medicine.On the graph,you can see epigenetic regulators under investigation or approved by the Food and Drug Administration(FDA),according to

39、 protein family.Eleven epigenetic agents are currently available for standard-of-care treatment:Three DNMT inhibitors(azacitidine,decitabine,hydralazine)Five HDAC inhibitors(belinostat,panobinostat,vorinostat,romidepsin,chidamide,the last one approved only in China)Two IDH inhibitors(enasidenib,ivos

40、idenib)One HMTi-EZH2 inhibitor(tazemetostat)Many more inhibitors of writers,erasers,and readers are in development.Rise of EpiDrugs DevelopmentDeep Pharma Intelligence14As of today,2153 clinical trials with approved EpiDrugs have been reported on ClinicalTrials.gov.653 of those clinical trials are a

41、ctive/recruiting patients.The biggest number of studies were started in the last decade:1110 clinical trials have been registered since 2015.The most popular drug is Azacitidine.From 2020 to nowadays,204 clinical trials have been using azacytidine alone or in combination or with other treatments.Dec

42、itabine,Panobinostat and Chidamide are the next most popular EpiDrugs in clinical studies.Sources:ClinicalTrials.govEpiDrugs in Cancer Clinical TrialsDeep Pharma Intelligence15YearAs of 2022,the percentage of clinical trials with approved EpiDrugs is negligible compared to trials with other drugs in

43、 treating cancer.Of these,only 10%have reached Phases 3 and 4,the stages at which industry-ready products are feasible in the nearest future.However,here we did not include all other EpiDrugs,that were not approved before.Therefore,the role of the development of EpiDrugs in the treatment of cancer s

44、hould not be neglected nowadays.Share of EpiDrugs Clinical Trials in ancer(86,478 trials)Total Number of Approved EpiDrugs Clinical Trials(2227 trials)YearNumber of Clinical TrialsYearNumber of Clinical TrialsSources:ClinicalTrials.govGrowth of Scientific Interest in EpiDrugs Deep Pharma Intelligenc

45、e16Total Scientific Interest in the EpiDrugs DevelopmentPredicted data to the end of 2022Number of PublicationsPopularity of Epigenetic Targets in Time5000Broadly speaking,scientific interest in epigenetic drugs and epigenetics growths through the years.Most papers investigate classic epigenetic tar

46、gets such as DNA Methyltransferases(DNMT1,DNMT3a and DNMT3b),and Histone deacetylases(HDAC1 and HDAC3).These targets are very reliable,and a few already FDA-approved drugs target these enzymes.However,the interest in non-classical targets such as Histone acetyltransferase KAT2B is also very perspect

47、ive and can bring the new first-in-class drugs.Sources:,Key Market PlayersDeep Pharma Intelligence17Key CompaniesKey R&D Centers(Academia)Big Pharma Players(113 programs)(20 programs)(8 programs)(9 programs)(8 programs)(7 programs)(25 programs)(35 programs)(13 programs)Key companies are evaluated ba

48、sed on the number of clinical trials with epigenetic drugs.These companies and R&D centres develop new epigenetic drugs,conduct the clinical trials of existing epigenetic medications for different conditions(various cancer types,cancers in special population groups,cancers with specific mutations,et

49、c.),and conduct the clinical trials of existing epigenetic drugs in combination with other treatments.(20+programs)(130+programs)(300+programs)(30+programs)(25+programs)(20+programs)(20+programs)(200+programs)(14 programs)(11 programs)(210 programs)(114 programs)(26 programs)(76 programs)(11 program

50、s)(25+programs)Selected Collaborations18Deep Pharma IntelligenceCollaboratorPharma CorporationsCollaborator Note:the central column defines the pharmaceutical corporations and side columns define companies and R&D centres that have collaborations with pharma companies from the central column.EpiDrug

51、 RepurposingDeep Pharma Intelligence19The typical process for EpiDrug development is time-consuming and costly.As a result,medication repositioning or repurposing,a promising technique for EpiDrug development,is focused on tracing novel potential epi-targets in already authorized pharmaceuticals.Due

52、 to a large number of repositioned candidate molecules that have previously undergone clinical and toxicity profiling studies,the medication repositioning technique is becoming more popular.The increased availability of biomedical data,particularly genomic data,which includes numerous elements of ce

53、llular systems,has fueled this method,allowing for a search that is not limited to biological components implicated in a disease.Source:Montalvo-Casimiro M,Gonzlez-Barrios R,Epidrug Repurposing:Discovering New Faces of Old Acquaintances in Cancer Therapy.Front.Oncol.(2020)Drug repurposingNew treatme

54、nt for a common diseaseNew treatment for a rare diseaseNew treatment for a neglected diseaseComputer analysis&AIScreening drug librariesLiterature reviewDeep Pharma Intelligence20Examples of EpiDrug RepurposingSource:Montalvo-Casimiro M,Gonzlez-Barrios R,Epidrug Repurposing:Discovering New Faces of

55、Old Acquaintances in Cancer Therapy.Front.Oncol.(2020)Resveratrol,commonly used for high cholesterol,cancer,and heart disease,has been postulated as a dual DNMT and HDAC inhibitor.Resveratrol suppresses both HDAC and DNMT1 activity in breast cancer cell lines,as well as histone H3 lysine 27 methylat

56、ion and acetylation.Chlorogenic acid may be responsible for the beneficial effects of coffee on glucose regulation and the development of type 2 diabetes.Chlorogenic acid has been proven in breast cancer cell lines to block DNMT1,lowering DNA methylation.5-azacytidine and 5aza2deoxycytidine(decitabi

57、ne)were the first repurposed pharmaceuticals in the area as anticancer EpiDrugs.These medications were first authorized by the FDA to treat myelodysplastic syndromes because of their antimetabolic actions in cancer cells in vitro experiments.Azacytidine and decitabine were later discovered to preven

58、t DNA methylation and were incorporated by tumor cells as well as in myelodysplastic syndromes.Green tea(Camellia sinensis)contains a polyphenol called EGCG,which is an anti-inflammatory substance.It has recently been proposed as a DNMT inhibitor that interacts directly with the DNMT catalytic site.

59、Platycodi radix(Platycodon grandiflorum),often known as balloon flower,is used to cure a variety of obesity-related disorders in East Asia.Ginseng and platycodi have recently been shown to have high HDACi action in lung cancer cell lines,upregulating p21 gene expression and causing cell death.Soybea

60、n,barley,wheat,and rye all contain lunasin,a 43-amino-acid peptide.Lunasin has been found in previous research to inhibit cancer cell proliferation and migration while having no effect on wild-type cells.HATs are inhibited by Lunasin,affecting the cell cycle and suppressing histone acetylation.Lunas

61、in ResveratrolPlatycodi radixChlorogenic acidEGCG5-azacytidineLongevity.InternationalEpigenetics and CancerDEEP PHARMA INTELLIGENCE22The Biological Basis of CancerDeep Pharma IntelligenceCancer is caused by the somatically heritable dysregulation of genes controlling cell division,death,and movement

62、 from one place of the body to another.During carcinogenesis,genes can become activated in a way that promotes cell division or prevents cell death(oncogene).Genes can also become inactive,meaning they are no longer able to put a stop to these activities(tumor-suppressor gene).Cancer develops as a r

63、esult of the interaction between these two types of genes.Signalling gene(oncogene)mutations in many human cancers are often dominant and drive the formation of cancers.Most oncogenes begin as proto-oncogenes,which are normal genes involved in cell growth and proliferation or apoptosis inhibition.No

64、rmal genes that promote cellular growth are up-regulated by mutation(gain-of-function mutation)and predispose the cell to cancer.Tumor-suppressor genes(TSGs)can be inactivated in at least 3 ways:(1)through mutations,which disable their functions;(2)a gene can be completely lost and thus not availabl

65、e to work properly(loss of heterozygoity);and(3)a gene can be switched off in a somatically heritable manner by epigenetic changes,rather than by mutation of the DNA sequence.Source:Baylin,S.B.,&Jones,P.A.Epigenetic Determinants of Cancer.Cold Spring Harbor perspectives in biology.(2016)Proto-oncoge

66、ne(overactivity mutation)Normal cellActivating mutation enables oncogene to stimulate cell proliferationNormal cellTumor suppressor gene(underactivity mutation)No effect of mutation in one gene copyTwo inactivating mutations functionally eliminate the tumor suppressor geneDeep Pharma Intelligence23H

67、allmarks of CancerEnabling Replicative ImmortalityActivating Invasion and MetastasisOne of the most prominent characteristics of cancer is its ability to invade and grow in distant tissues,which is dependent on changes in cancer cells interactions with their environment.Inducing AngiogenesisResistin

68、g cell deathTumour-promoting InflammationCancer cells hijack inflammatory mechanisms to promote their own growth and survival.It helps to promote and develop all stages of tumorgenesis.Avoiding Immune ResponseThe developing tumor tissue need more oxygen and nutrients,therefore it must release pro-an

69、giogenic signals to encourage the development of new blood vessels.Sustaining proliferative signallingMalignant cells rely on the telomerase enzyme to keep the length of their telomeres above a key threshold that allows them to keep dividing in order to become immortal.Apoptosis is a crucial antican

70、cer barrier,as immortality is another mechanism for cancer cells to multiply.Normal cells rely on external growth signals to proliferate,whereas cancer cells can produce most of their own growth signals,reducing or eliminating their dependency on external stimuli.Evading Growth SuppressorsCancer cel

71、ls escape antiproliferative signals by manipulating cell cycle regulatory mechanisms,such as altering the pRb pathway.Genome Instability and MutationsCancer frequently results from damage to genes controlling cell division and tumor suppressors.The genome instability and mutations are highly connect

72、ed with epigenetic changes.Some cancer cells develop mechanisms to avoid identification and killing by the immune system.One method cells do this is by using STING to hijack normal immunological regulation.Source:Douglas Hanahan and Robert A Weinberg(2011).Hallmarks of cancer:the next generation.Cel

73、l.The Epigenetics of CancerDeep Pharma Intelligence24One of the ways to inactivate tumor-suppressor genes is by epigenetic changes,rather than by mutation of the DNA sequence.Epigenetic silencing can occur by deregulation of the epigenetic machinery at several different levels;1)it may involve inapp

74、ropriate methylation of cytosine(C)residues in CpG sequence motifs that reside within control regions governing gene expression.2)changes to histone posttranslational modifications(PTMs)or aberrations in the way histone-modifying enzymes function may occur,3)change in a proteins ability to read hist

75、one marks,and hence bind to chromatin,or alterations in the way nucleosome-remodeling or histone exchange complexes function can result.Finally,changes in regulatory microRNA(miRNA)expression patterns have been noted.There is constant research on how epigenetic silencing affects cancer prevention,de

76、tection,and treatment.The FDA has recently approved medications to reverse epigenetic alterations and restore gene function in cancer cells.Furthermore,because changes in DNA methylation can be identified with great sensitivity,there are numerous ways to detect cancer in its early stages just by loo

77、king for changes in DNA methylation.As a result,the potential for epigenetics to be used in human cancer research,detection,prevention,and therapy is enormous.Source:Baylin,S.B.,&Jones,P.A.Epigenetic Determinants of Cancer.Cold Spring Harbor perspectives in biology.(2016)Gene Expression PotentialNuc

78、leosome remodelingHistones and variantsmiRNAsHistone PTM readersHistone-modifyingDNA methylationH3K27 mutantH3K34 mutantBRD4,TRIM33,ING1,BRCA1SNF5,BRG1/BRM,ARID,ATRX DNMT1,DNMT3A,TET,IDH,MBDs MLL,SETD2,EZH,JARID1C,UTX,BMI1,LSD1The Role of DNA Methylation in CancerDeep Pharma Intelligence25Over the l

79、ast 40 years,studies have shown that changes in the distribution patterns of 5-methylcytosine(5mC),also known as the 5th base,can identify cancer cells from normal cells.At least three key pathways for CpG methylation to contribute to the oncogenic phenotype have been identified.1)by general hypomet

80、hylation of the genome.2)TSG promoters may experience localized hypermethylation.3)Deamination,UV irradiation,or exposure to other carcinogens can all be used to cause direct mutagenesis of 5mC-containing sequences.Notably,all three of these changes tend to happen at the same time and lead to cancer

81、,implying that epigenetic homeostasis is crucial to the evolution of human cancer.To fuel cancer growth,the link between genetic disruptions and epigenetic abnormalities is mutually advantageous,and it might be playing a crucial role in individual variances in how patients respond to medicines in te

82、rms of toxicity and treatment efficacy.De novo EpiDrugs and EpiDrug repurposing have been shown in several studies to resensitize cancer cells to chemotherapy by reversing epigenetic changes.Source:Baylin,S.B.,&Jones,P.A.Epigenetic Determinants of Cancer.Cold Spring Harbor perspectives in biology.(2

83、016),BThe Role of DNA Methylation in CancerDeep Pharma Intelligence26DNA HypomethylationDNA HypermethylationDNA demethylation has been linked to aneuploidy and genomic instability,both of which are cancer hallmarks.When the maintenance DNA methyltransferase,Dnmt1,is deleted or decreased,increased mu

84、tation rates,aneuploidies,and tumor formation are seen,demonstrating that DNA hypomethylation plays a role in promoting chromosomal fragility.The aberrant hypermethylation of CpG islands in the 5 regions of cancer-related genes is a well-known DNA methylation alteration in cancer.This alteration may

85、 be linked to transcriptional silence,giving an alternative to mutation for inactivating tumor-suppressor genes,which usually prevents cells from stopping the cancerous growth.Source:Baylin,S.B.,&Jones,P.A.Epigenetic Determinants of Cancer.Cold Spring Harbor perspectives in biology.(2016),BGenesNorm

86、al MethylomeCancer MethylomeHypomethylated DomainHypomethylated DomainHypermethylated CpG IslandDense methylationNot dense methylationDNMTs Inhibitors27IncorporationNucleoside inhibitorsMetabolized and phosphorylated to deoxynucleotide triphosphates and incorporated into DNA.DNMT recognizes the modi

87、fied bases as natural substrate,the enzyme becomes trapped and subsequently is been degraded.RG108,S110,MG98Blocking the active siteProcainamide Procaine HydralazineBlocking the active siteNon-nucleoside inhibitorsNon-nucleoside inhibitors either block the DNMTs enzyme catalytic site or interact wit

88、h enzyme recognition of target sequences.Although several non-nucleoside agents also possessDNA-demethylating activity.Rationally designed inhibitorsThe popularity of rationally designed inhibitors,a new strategy for inhibiting DNMTs based on small compounds,is growing.They can directly and specific

89、ally blocks the active site of DNMTs.AzacytidineDecitabineZebularineGuadecitabineDeep Pharma IntelligenceInhibiting DNMTs with demethylating drugs can efficiently reactivate previously epigenetically repressed genes.In general,there are three types of DNA methylation inhibitors:nucleoside inhibitors

90、,non-nucleoside inhibitors,and rationally designed inhibitors.Source:Magic et al(2009).Journal of B.U.ONDNMTThe Importance of Chromatin to CancerDeep Pharma Intelligence28From the recent research,its clear that epigenetic regulation affects not only canonical coding genes,but also noncoding RNA(ncRN

91、A),microRNAs(miRNAs),and other genome regulatory areas.Thousands of tumors have been examined,revealing,an unexpected abundance of mutations in genes that affect epigenome activity.Several of these mutations occur often enough in tumors to support their roles as driver mutationsthat is,the findings

92、suggest that mutations disrupting the epigenome may contribute to cancer start and development.Recent genomic alterations on epigenetic modulators were revealed by the mutational fingerprints of human malignancies.A wide range of cellular activities essential for carcinogenesis and tumor growth is o

93、rchestrated by cancers dependence on the epigenome,potentially facilitating escape mechanisms that result in treatment resistance.Epigenetic changes in cancer can occur independently of chromatin-modifying factor mutations;the epigenome is also vulnerable to damage and heritable alterations brought

94、on by physiological or environmental events that are part of cancer risk states and steps in the progression of cancer.Chromatin remodeling factors control how cellular factors interact with target DNA,any disruption or dysregulation of these special machinery is anticipated to alter the transcripto

95、me status to a malignant state.Source:Baylin,S.B.,&Jones,P.A.Epigenetic Determinants of Cancer.Cold Spring Harbor perspectives in biology.(2016),BClosed ChromatinOpen ChromatinHistone Deacetylase(HDAC)Histone Acetyltransferase(HAT)HDACs InhibitorsDeep Pharma Intelligence29The acetylation level of hi

96、stones in chromatin and a variety of non-histone substrates,such as several proteins implicated in tumor development,cell cycle regulation,apoptosis,angiogenesis,and cell invasion,are regulated by the HDAC family of enzymes(histone deacetylases).There are 18 genes in the HDAC family,which are divide

97、d into classes I,II,III,and IV.HDAC inhibitors primarily target classes I,II,and IV HDACs,which are considered to be classical HDACs since they have a Zn2+catalytic ion in their active site rather than class III HDACs,which have NAD+as a necessary cofactor.Specificity to Class ISpecificity to Class

98、IISpecificity to Class IVValproic acidEntinostatMocetinostatRomidepsinPanobinostatAbexinostatBelinostatPanobinostatVorinostatMocetinostatQuisinostat BelinostatPanobinostatNote:Selected EpiDrugs that are related to HDACi and are in development or are currently on the market.Here you can see also comp

99、anies that are mainly involved in their development,but there are several others.Diverse drugs can target two or three classes of HDACs at the same time.Other Epigenetics TargetsDeep Pharma Intelligence30Isocitrate dehydrogenase(IDH)Histone methyltransferase(HMT)Poly(ADP-ribose)polymerase(PARP)Targe

100、tDescription#of DrugsIDH is involved in the conversion of isocitrate to-ketoglutarate(-KG).IDH mutation produces a neomorphic enzyme,which inhibits histone and DNA demethylases,resulting in hypermethylated histones and DNA,altering gene expression and driving cancer progression.HMTs are a class of e

101、nzymes that mediate the methylation of lysine or arginine residues of histones.Some enzymes tend to have a mutation in cancers,which enhances their activity.Inhibitors target both mutant and wild-type forms of the protein to induce cell cycle arrest and apoptosis of lymphoma cells in preclinical mod

102、els.PARP is a family of proteins involved in several cellular processes such as DNA repair,genomic stability,and programmed cell death.PARPs catalyze the addition of ADP ribose units from“nicotinamide adenine dinucleotide-donor molecules”to their target substrates.This reaction is essential for DNA

103、methylation.Approved:2 In clinical trials:2Approved:1 In clinical trials:9In clinical trials:2CompaniesOther Epigenetics TargetsDeep Pharma Intelligence31Histone demethylasesBromodomain and extraterminal(BET)Histone kinaseTargetDescription#of DrugsAberrant expression of histone lysine demethylases h

104、as been documented in many types of blood and solid tumors,and thus demethylases represent promising therapeutic targets.Additionally,aberrant histone methylation helps oncogenic drivers accelerate cancer progression,metastasis,and therapy resistance.Epigenetic reader proteins BET are known to drive

105、 stem cell development,cellular identity,and transitions between mature cell states.In cancer BET regulate the expression of multiple genes involved in carcinogenesis.BET inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers.Histone phosphorylation and dephosphor

106、ylation by kinases and phosphatases has emerged as an important mechanism for the regulation of diverse events involving chromatin,including transcription,DNA replication,chromosome segregation,DNA damage,and apoptotic responses.In clinical trials:4In clinical trials:10In clinical trials:1CompaniesM

107、ain Developers of Epigenetics Targets Deep Pharma IntelligenceHDAC class IHDAC class IIHDAC class IV Treatment products HDACiTreatment products DNMTiTreatment products IDHiTreatment products Note:Therapeutic target medicines that are in development or are currently on the market are presented here.I

108、t is evident that HDACi are the primary focus of study and development.Other fields are actively growing,but because of the high complexity,most of them are not yet marketed.Treatment products PARPiTreatment products HDMiHMTiDNMT1DNMT3ADNMT3 IDH1IDH2KDM1KDM2KDM4KDM15PARP1PARP2EZH2PRMT1PRMT5Treatment

109、 products BETiBRD2BRD3BRD4BRDTData based according to reported clinical trials32Combination TherapyAll of the identified hallmarks of cancer are influenced by epigenetic regulation,which can be addressed utilizing various treatment techniques.According to Hanahan and Weinberg,these hallmarks are ten

110、 biological qualities gained during oncogenesis that drive and/or enable the development of cancer.Various epi-drugs have the potential to improve the efficacy of four primary anticancer treatment pillars:genotoxic and/or cytotoxic treatments(including chemotherapy and radiotherapy),hormone therapy,

111、molecularly targeted therapy,and immunotherapy.Cancers change over time,in part due to fitness-enhancing dynamic and reversible epigenetic modifications.Epi-drugs may thus be most successful when combined with other treatments,and they present particularly interesting ways for sensitizing cancer cel

112、ls to specific therapy and dynamically overcoming accumulated resistance mechanisms.Deep Pharma Intelligence33Sources:Morel et al(2020).Nature Reviews Clinical OncologyHallmarks of CancerResisting to deathGenome instability and mutationsActivation invasion and metastasisInducing angiogenesisTumor-pr

113、omoting inflammationAvoiding immune responseDeregulating cellular energeticsSustaining proliferative signallingEvading growth suppressorsEnabling replicative immortalityImmunotherapyHDACi,HATi and/or BETi Reverse endocrine resistanceHormone therapyTargeted therapiesGenotoxic and/or cytotoxic chemo-a

114、nd radiotherapyDNMTi and/or HDACi Facilitate access to DNA Re-express tumour supressors Increase ROSDNMTi,EZH2i and/or LSD1i Differentiate cancer stem cellsEZH2i Sensitive to TOP2iBETi and/or PRMTi Decrease DDR capabilitiesDNMTi,HDACi and/or EZH2i Increase antigen presentation and chemokine and/or I

115、FN expressionDNMTi,HDACi and/or LSD1i Enable viral mimicry M2-M1 macrophage polarizationBETi Anti-inflammatoryDNMTi and/or HDACi Revert EMT HDACi Promote HIF1a degradation Reduce oncoprotein stabilityBETi Prevent oncogene transcriptionCombination of EpiDrugs with Immunotherapy to Treat CancerAntitum

116、or immunity is the result of a complicated interaction of immune,cancer,and stromal cells.Specific DNA-modifying or histone-modifying enzymes,such as DNMTs and HDACs and chromatin assembly factors have a role in cancer cell immunogenicity as well as immune cell lineage commitment and maturation.In p

117、reclinical models,epigenetic alterations can reverse several pathways of resistance to immune-checkpoint inhibitors(ICIs).As a result,epi-drugs could be employed to modify antitumor immunity.Some recent clinical studies highlight the potential of combining epi-drugs with ICIs,particularly in tumors

118、resistant or refractory to ICIs.Pembrolizumab(anti-PD-1antibody)Entinostat(HDACi)Advanced StudyResults of phase Ib/II trialPartial response:-1 patient with microsatellite-stable Colorectal cancer-9 patients with ICI-resistant melanoma-7 patients with ICI-resistant Non-small cell lung cancerComplete

119、response:-1 patient with ICI-resistant melanomaDNMTi,HDACi and/or EZH2i:Increase antigen presentation and chemokine and/or IFN expressionDNMTi,HDACi and/or LSDi:Enable viral mimicryBETi:Anti-inflammatory.Deep Pharma Intelligence34Clinical Trials of EpiDrugs in Combination with ImmunotherapySources:C

120、linicalTrials.govCombination of EpiDrugs with Hormone Therapy to Treat CancerInvasive breast cancer has been on the rise since 2004,with over two million cases recorded worldwide in 2018,and over 270,000 cases expected in the United States in 2020.Small drugs targeting chromatin regulators may re-se

121、nsitize resistant cells to endocrine therapy or boost sensitivity to novel treatments by remodeling the cancer epigenome.The key oncogenic driver of 70%of breast cancers is the oestrogen receptor(ER).HDAC inhibitors have been proven in preclinical studies to improve the antitumor efficacy of hormone

122、 treatments or reverse resistance to them in ER-positive breast cancer living creatures.In combination with the anti-oestrogen fulvestrant,BETi inhibits the growth of tamoxifen-resistant tumor cells and xenografts.ExemestaneEntinostat(HDACi)Advanced StudyExemestane may help to prevent Breast Cancer

123、by reducing the amount of estrogen produced by tissue aromatase.Entinostat may assist overcome tumor resistance via epigenetic alterations,enhancing the anti-tumor efficacy of exemestane in Breast Cancer.A previous Phase II trial in US Breast Cancer patients found that combination therapy had a subs

124、tantial effect on reducing disease progression and improving patient survival.Phase III trial is ongoingHDACi,HMTi and/or BETi:reverse endocrine resistanceDeep Pharma Intelligence35Clinical Trials of EpiDrugs in Combination with Hormonal TherapySources:ClinicalTrials.govSynergy has generally been ob

125、served with DNA-damaging compounds in preclinical investigations evaluating the effects of epi-drugs in conjunction with chemotherapy.HDAC inhibitors and DNMT inhibitors cause global chromatin relaxation,which allows genotoxic chemicals to damage DNA more easily and interferes with DNA repair.In add

126、ition,low-dose combinations of HDAC inhibitors and DNMT inhibitors may revert cytotoxic drug resistance,in part by removing accumulated epigenetic changes that underlie the resistance phenotype.Other third-generation epi-drugs,such as BET inhibitors,interfere with DNA repair processes as well,boosti

127、ng the risk of cytotoxic therapeutic synergy.Combination of EpiDrugs with hemotherapy to Treat CancerTemozolomide or BevacizumabVorinostat(HDACi)Advanced StudyDNMTi and/or HDACi:Facilitate access to DNA,re-expression of epigenetically silenced genesBETi:Decrease DNA repair capabilitiesDeep Pharma In

128、telligence36A randomized phase II/III trial is studying Vorinostat,Temozolomide,or Bevacizumab to see how well they work compared with each other when given together with Radiation therapy followed by Bevacizumab and Temozolomide in treating young patients with newly diagnosed High-Grade Glioma.It i

129、s not yet known whether giving Vorinostat is more effective than Temozolomide or Bevacizumab when given together with Radiation Therapy in treating glioma.RadiotherapyClinical Trials of EpiDrugs in Combination with ChemotherapySources:ClinicalTrials.govCombination of EpiDrugs with Radiotherapy to Tr

130、eat CancerHDAC,DNMT,EZH2,or BET inhibition force the antitumor effect of radiation in preclinical trials by interrupting the cell cycle,as well as increasing oxidative stress.In mouse models,BET inhibition reduces the risk of radiation-induced lung fibrosis and has a radioprotective impact on irradi

131、ated non-malignant lung tissue in vitro.However,combining HDAC inhibitors with radiation has mostly resulted in higher toxicity and minimal patient benefit in clinical trials.Certain DNMT inhibitors,such as 5-azacytidine,can be integrated into DNA and/or RNA,making them particularly potent radiosens

132、itizers in all tissues.Therefore,using these epi-drugs with radiotherapy is not suggested due to toxicity concerns.131I-MIBGVorinostat(HDACi)Advanced StudyThis combination in children with Relapsed and/or Refractory High-risk Neuroblastoma led to an ORR of 12%at all dose levels and 17%at the recomme

133、nded phase II dose.The results of phase II trial show that Vorinostat and MIBG is likely the arm with the highest true response rate,with manageable toxicity.DNMTi and/or HDACi:Facilitate access to DNA,Increase ROSBETi:Decrease DNA repair capabilitiesEZH2:Sensitive to TOP2iDeep Pharma Intelligence37

134、Clinical Trials of EpiDrugs in Combination with RadiotherapySources:ClinicalTrials.govDNMTi and/or HDACi:Revert epithelial-mesenchymal transitionHDACi:Promote HIF1a degradation,Reduce oncoprotein stabilityBETi:Prevent oncogene transcriptionCombination of EpiDrugs with Targeted Therapies to Treat Can

135、cerResistance to medicines targeting HER family receptor tyrosine kinases can be epigenetically induced and consequently reverted by EpiDrugs,according to preclinical research.Several early-stage clinical trials have been done to assess the safety of HDAC inhibitors and anti-angiogenic medicines in

136、combination.Combinations of HDAC inhibitors and inhibitors of the PI3KAKTmTOR pathway have shown promise in preclinical investigations.Pazopanib Abexinostat(HDACi)Advanced StudyDeep Pharma Intelligence38This is a randomized,Phase 3,placebo-controlled study in patients with locally Advanced Unresecta

137、ble or Metastatic Renal Cell Carcinoma(RCC).A phase 1b study demonstrated strikingly durable responses in patients with RCC.Induction of histone acetylation in peripheral blood mononuclear cells was associated with a durable treatment response.The addition of Abexinostat to Pazopanib could significa

138、ntly improve outcomes in patients with clear cell RCC.Clinical Trials of EpiDrugs in Combination with Targeted TherapiesSources:ClinicalTrials.govDNMTi:causes hypomethylation of DNAIGHi:Inhibits mutant IDH to stop the reduction of-ketoglutarate(-KG)to 2-hydroxyglutarate(2-HG)Combination of Different

139、 EpiDrugs to Treat CancerMany studies investigate the combination of different epigenetic drugs to treat cancer.Additionally,the cooperation of varying types of epigenetic medicines and other treatments(for example,immunotherapy,chemotherapy,cell transplantation,etc.)are also actively studied.The mo

140、st actively are studying the combination of DNMT inhibitors with HDAC inhibitors.Mainly this combination is used for the treatment of blood cancers.Clinical trials look at the effectiveness of this combination in different age groups,patients with specific mutations and special disease conditions(fo

141、r example,recurrent disease).Azacitidine(DNMTi)Ivosidenib(IGHi)Advanced Study-Deep Pharma Intelligence39Clinical Trials of Different EpiDrugs CombinationSources:ClinicalTrials.govThis is a placebo-controlled clinical trial(Phase III)to evaluate the efficacy and safety of Ivosidenib+Azacitidine vs pl

142、acebo+Azacitidine in adult participants with previously untreated Acute Myeloid Leukemia.Preliminary data shows that median overall survival was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine and estimated probability that a patient would remain event-free at

143、 12 months was 37%in the ivosidenib-and-azacitidine group and 12%in the placebo-and-azacitidine group.Longevity.InternationalEpigenetics and AgingDEEP PHARMA INTELLIGENCEDeep Pharma Intelligence41Hallmarks of AgingAgeing can be the consequence of increased DNA damage accumulation.This is due to phys

144、ical,chemical,and biological agents,as well as DNA replication errors,spontaneous hydrolytic reactions,and reactive oxygen species(ROS).Genomic InstabilityCellular senescence can be defined as a stable arrest of the cell cycle.The accumulation of senescent cells in aged tissues can lead to age-relat

145、ed disease progression.Cellular SenescenceStem Cell ExhaustionTelomeres are the chromosomal regions located on the ends of chromosomes.They tend to become increasingly shorter after each DNA replication.When this sequence ends,the cell dies.Telomerase deficiency in humans is associated with age-rela

146、ted diseases.Telomere AttritionEpigenetic AlterationAltered Intercellular CommunicationProteostasis involves mechanisms for the stabilization of correctly folded proteins,and the heat-shock family of proteins,as well as mechanisms for the degradation of proteins.These processes tend to change during

147、 ageing.Loss of ProteostasisDeregulated Nutrient SensingEpigenetic changes involve alterations in DNA methylation,post-translational modification of histones,and chromatin remodeling.Nutrient sensing includes trophic and bioenergetic pathways,such as insulin and IGF-1,signaling pathways,and other sy

148、stems(mTOR,AMPK,and sirtuins).Mitochondrial DysfunctionThere is a noticeable reduction in ATP generation and increased electron leakage in the respiratory chain caused by ageing.Stem cells are cells from which all other cells with specialized functions are generated.There is a substantial decrease i

149、n the number of stem cells during life.Recent studies suggest that stem-cell rejuvenation may reverse the ageing phenotype.Neurohormonal signaling tends to be deregulated in ageing as inflammatory reactions increase,while immunosurveillance against pathogens and premalignant cells declines.Sources:L

150、pez-Otn C,Blasco MA,Partridge L,Serrano M,Kroemer G.The hallmarks of aging.Cell.2013The Aging Epigenome Deep Pharma Intelligence42Ageing is associated with functional decline in tissues and organs as well as increased risk of developing age-related disorders.The interventions delaying ageing include

151、 metabolic manipulation,partial reprogramming,heterochronic parabiosis,pharmaceutical administration and senescent cell ablation.Changes in DNA methylation,histone post-translational modification,and chromatin architecture and remodeling impact healthspan and longevity,according to recent animal res

152、earch.Since the ageing process is associated with altered epigenetic mechanisms of gene regulation,such as DNA methylation,histone modification and chromatin remodeling,and non-coding RNAs,the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions.Source:Zhang

153、,W.,Qu,J.,Liu,GH.et al.The ageing epigenome and its rejuvenation.Nat Rev Mol Cell Biol 21,137150(2020)Genomic instabilityMitochondrial malfunctionMetabolic imbalance Chronic inflammationAccumulation of senescent cells and SASPStem cell exhaustionAgeingRejuvenationYoungOldHeterochromatinEuchromatinAc

154、MeMeHP1Balance between heterochromatin and euchromatinHistone modificationDNA MethylationChromatin remodellingDeep Pharma Intelligence43Epigenetic Biomarkers for AgingKey CompaniesFinding accurate aging biomarkers is a fundamental goal in modern geroscience.As the aging process is closely associated

155、 with altered epigenetic mechanisms,epigenetics biomarkers have become an interesting research object.The hypo-and hyper-methylation changes in many regions across the genome have the potential to predict biological age.Epigenetic clocks are age-related indicators based on DNA methylation levels at

156、a subset of CpG sites.The difference between age indicated by these clocks and chronological age,termed epigenetic age acceleration,has been shown to predict age-related disease and mortality.The first generation of the epigenetic aging clocks was developed using chronological age as a surrogate for

157、 biological age.The new generation of epigenetic clocks,DNAm PhenoAge,incorporated composite clinical measures of phenotypic age that capture differences in lifespan and healthspan and,besides biological age prediction,can also predict forecasts for a variety of aging outcomes,including all-cause mo

158、rtality,cancers,healthspan,physical functioning,and Alzheimers disease.This set of biomarkers is able to capture risks for an array of diverse outcomes across multiple tissues and cells and provide insight into essential pathways in aging.Many companies are trying to create reliable epigenetic clock

159、s because it enables the evaluation of interventions to promote healthier aging.Source:Clinical Epigenetics Deep Pharma Intelligence44Biomarkers of Human LongevityDmitry Kaminskiy,co-founder and managing partner of Deep Knowledge Group,published a series of books dedicated to the topic of Human Long

160、evity.One of the most intriguing is“Biomarkers of Human Longevity”.That book placed particular emphasis on the power that Biomarkers of Human Longevity have to serve as a major catalyst and accelerator of short-term practical applications,the translation of theory into practice.Biomarkers of Human L

161、ongevityLongevity Industry 1.0Longevity PoliticsLongevity Financial IndustryPractical LongevityLongevity Industry 2.0To learn more about the books:https:/www.longevity- ReportsDeep Pharma Intelligence45Aging Analytics Agency is the worlds premier provider of industry analytics on the topics of Longe

162、vity,Precision Preventive Medicine and Economics of Aging,and the convergence of technologies such as AI,Blockchain,Digital Health and their impact on the healthcare industry.Aging Analytics Agency published a series of reports dedicated to longevity industry in in various manifestations.To learn mo

163、re about the reports:https:/ Biomarkers Landscape Overview,Q1 2022 Mitochondria in Longevity and Space Medicine,Q3 2021 Longevity Industry in Switzerland Longevity Clinical Trials,Q3 2021VR in Medical Practice,Q1 2022Regenerative medicine,Q1 2022Deep Pharma Intelligence46Epigenetics in Neurodegenera

164、tive DiseasesEnvironmental variables have a significant impact on neurodegenerative disorders including Alzheimers disease(AD),Parkinsons disease(PD),Huntingtons disease(HD),Prion disease,and others;thus,modifications in the epigenome are implicated.Neuroepigenetics refers to the study of epigenetic

165、s in neurons.Alzheimers diseaseParkinsons diseaseMethylationLimited 5mC,5Fc,5hmC,and 5caC signatures in AD lead to neuronal degeneration.With age,methylated cytosines in 207182 area get demethylated resulting in the deposition of A in the brain.Reduction of DNA methylation in intron 1 of SNCA was ob

166、served in PD patients.Increased level of SNCA expression is seen if DNA methylation is inhibitedHistone ModificationsMemory-related brain regions show greater concentrations of HDAC2&HDAC3.HDAC2 reduces the histone acetylation of the memory and learning-related genes.Increased HDAC6 was also found i

167、n AD patients with cognitive impairmentResponse to treatment with HDACi in disease modelsA-synuclein reduction in histone acetylation and histone gene expression.Micro RNA regulationmiRNAs aid in neurogenesis and amyloid processing during the development of AD.Brain-derived neuropathic factor,contro

168、lled by miR-206,may influence both synaptic plasticity and memory in a human AD brain.miR-7 and miR-153,found in the PD patients,together regulate the concentration of-synuclein,required for synaptic vesicle trafficking and subsequent neurotransmitter release.Source:P.Ghosh,A.Saadat,Neurodegeneratio

169、n and epigenetics:A review,Neurologa,(2021)Deep Pharma Intelligence47Clinical Trials on Epigenetics Drugs for Neurodegenerative DiseasesSource:OVafidemstat (ORY-2001),a CNS optimized covalent LSD1 inhibitor for neurological disorders.Vafidemstat restores memory to normal levels and reduces the exace

170、rbated aggressiveness in a model for accelerated aging and Alzheimers disease(AD)as well as reduces neuroinflammation in multiple sclerosis(MS).Lysine-specific demethylase LSD1 plays a fundamental role in neurogenesis,neuronal differentiation and axonal navigation.LSD1 is the most abundant Lysine De

171、methylase in the prefrontal cortex.Currently in Phase IIa for:1.Assessment of Vafidemstatseffect on agitation-aggression in patients with different psychiatric disorders(REIMAGINE study)2.Testing aggressive/agitated patients with moderate or severe Alzheimers disease(REIMAGINE-AD study)3.ETHERAL and

172、 ETHERAL-US studies in patients with mild to moderate Alzheimers diseaseCurrently in Phase IIb:1.Ongoing study of vafidemstat in Borderline Personality Disorder patients(PORTICO study)2.Evaluation of vafidemstats efficacy on negative symptoms and cognition in schizophrenia patients3.Vafidemstat is a

173、lso being evaluated in severely ill COVID-19 patients(ESCAPE study),assessing the capability of the drug to prevent Acute Respiratory Distress Syndrome(ARDS),(the most severe complications of the viral infection).Clinical trials of VafidemstatDeep Pharma Intelligence48Epigenetics in Cardiovascular D

174、iseasesThe first Phase 3 BET inhibitor linical trial conducted outside of oncology is called BETonMACE.The trial,which was completed in September 2019,was created to assess the safety and effectiveness of apabetalone in reducing Major Adverse Cardiac Events(MACE)in high-risk patients with type 2 dia

175、betes mellitus who had cardiovascular disease.Apabetalone is an epigenetic drug that treats vascular diseases by reducing the expression of genes associated with the ailment.Patients with diabetes and vascular disease who express these genes have a faster progression of their conditions,which damage

176、s their arteries and raises their risk of heart attacks and strokes.Apabetalone normalizes expression towards a healthier state by preventing specialized proteins known as bromodomain and extraterminal domain(BET)proteins from activating the expression of disease-associated genes.Genome editingThere

177、 are currently no FDA-approved therapies based on gene editing.Transcriptional regulationApabetalone,acting upstream of traditional pharmaceuticals,represents a paradigm shift in the treatment of chronic disease.Protein inhibitionAlmost all current therapeutics function via protein inhibition.Source

178、s:ReverselogixDNARNAProteinTranscriptionTranslationLongevity.InternationalMarket OverviewDEEP PHARMA INTELLIGENCERegional DistributionDeep Pharma Intelligence50USA51%Canada2%UK6%EU23%China8%Asia10%Most companies conducting research and development of epigenetics drugs are located in the United State

179、s(51%).The second place is Europe(23%),where the most active countries are Germany and Switzerland.The Asian region also has many developments in this direction:overall,Asia has 18%of companies developing the epigenetic drugs,and 8%of them are in China.Categorical DistributionDeep Pharma Intelligenc

180、e5142%HDACi26%DNMTiPARPiBETiHMTiHDMiIDHi16%7%5%3%42%26%16%7%5%3%The epigenetic drug discovery field has evidenced significant advancement in recent times.The majority of companies conducting EpiDrug development are focused on HDACi,which accounts for 42%of the clinical trials analysed companies.DNMT

181、i is in second place,and 26%of clinical trials presented here aim to develop drugs which will target this class of enzymes.Surprisingly,16%of calculated clinical trials are tested PARPi,which are very popular among a few advanced companies.Other drugs that have fewer than 10%of clinical trials are H

182、MTi,IDHi and HDMi.3%Sources:ClinicalTrials.govThe comparison of the monthly cost of epigenetic drugs with other common chemotherapy agents showed that epigenetic drugs prices are,on averagely,four times higher.Most costs were taken for 2015 and adjusted by the inflation rate.There are a few reasons

183、for the high prices of epigenetic drugs.One of the most significant is the high cost of the research and development of such drugs.Additionally,epigenetic drugs are relatively new;most of them were approved after 2010,when some other chemotherapy agents were more than 50 years on the market.That may

184、 note that companies had less time for manufacturer process adjusting to make it more cost-efficient.Epigenetic Drugs CostsDeep Pharma Intelligence52Epigenetic drugsAlkylating agentsPlant alkaloidsAntimetabolitesAnti-tumor antibioticsMonthly Cost of Epigenetic Treatment Compared to Other Chemotherap

185、y AgentsYear of Drug Approval 2020 2010-2020 2000-2010 2000Sources:Medical News Today,Memorial Sloan Kettering Cancer CenterR&D CentresDeep Pharma Intelligence53Distribution of R&D Centres by Country,%USA63%China25%Distribution of R&D Centres by Category,%The vast majority of R&D Centres that conduc

186、t mitochondria research are located in the United States,where 63%of the whole range of analysed R&D Centres are located.The United States is distantly followed by China and France which together make up 30%of all R&D Centers.The major domain in which epigenetics research are being conducted is DNMT

187、 inhibitors and HDAC inhibitors.More than half of main R&D centers conduct research in this field.DNMTiHDACiHKiPARPiIDHiFrance 5%Belgium 1.2%Germany 1.5%Switzerland 1.5%Italy 2.5%Mexico1.5%HDMiHMTiHMTiChallenges and Opportunities for Epigenetic Drug DiscoveryDeep Pharma Intelligence54TARGET SELECTIO

188、NCHEMICAL DESIGN,DRUG PRODUCTION,ENZYMATIC ASSAYSIN VIVO BIOLOGYCLINICAL TRIALSEnzyme isoform selectivityPTM modifications of histones vs non-histone substratesFunctional effect of inhibiting specific epigenetic modifiersOff-target effects on additional complex membersEffects on high-order chromatin

189、 structureDevelopment of reference compoundsDevelopment of isoform-selective inhibitorsDevelopment of dual inhibitorsProduction of active enzymes and specific substratesIn vitro assays based on nucleosome substrates may not fully recapitulate the effect of the drugProduction of active enzymes and sp

190、ecific substratesDose-limiting toxicitiesKinetics of the drug responseImproving the long-lasting effects of the drugPatient selection EpiDrugs for solid tumors/non-tumoral diseases/EpiDrugs in combination to improve immunotherapy/chemotherapy/radiotherapy/hormone therapy/target therapy treatmentsRed

191、uction of off-target effectsIsoform selective inhibitorsGenetic-engineering tools(CRISPR-Cas9,siRNAs)Multitarget compoundsDevelopment of new in vitro modelsDevelopment of robust throughput in vitro and cellular/phenotypic assaysDesign of focused chemical librariesImproved in silico ADME prediction t

192、oolsDevelopment of in vitro models closer to physiological context Development of new models(inducible knockout animals,organoids,humanized murine models)Biomarkers for prediction of drugs responseCombinatory therapy to minimize chemoresistanceActivating mutations as more targeted therapy Synthetic

193、lethal approachesSources:Ganesan et al(2019).Clinical Epigenecis.Epigenetic dysregulation has been acknowledged as a significant cause of human diseases for the recent decades.This is encouraged more research into the area of finding drugs for epigenetic disorders that are called EpiDrugs.EpiDrugs u

194、sually are small-molecule inhibitors that either target the epigenome or enzymes with epigenetic activity.The three categories of epigenetic regulators are targeted by EpiDrugs:writers,readers and erasers.Nevertheless,the implementation of EpiDrugs in clinical practice is very scarce.The biggest par

195、t of approved or tested in clinical trials EpiDrugs now are almost exclusively DNA methyltransferase(DNMT)inhibitors or histone deacetylase(HDAC)inhibitors.Nowadays,there are 11 EpiDrugs approved by FDA.Both pharmaceutical companies and R&D centres are involved in EpiDrug development,but most of the

196、 clinical trials registered to date are owned by pharmaceutical companies.Despite their promise,there are still many issues that need to be resolved before EpiDrugs can be effectively used to treat human cancer.These issues include the lack of specificity of EpiDrugs,their lackluster effectiveness i

197、n treating solid tumors,and their development of drug chemoresistance,which increases the risk of tumor relapse.Recent advancements highlight the significance of integrating EpiDrugs with non-epigenetic therapeutic agents to design better policies for the treatment of cancer and non-cancer disorders

198、.Deep Pharma Intelligence55Key TakeawaysAzacitidineDecitabineVorinostatRomidepsinBelinostatHydralazinePanobinostatChidamideEnasidenibIvosidenib56Deep Pharma IntelligenceApproved(2004)Approved(2006)Approved(2006)Approved(2009)Approved(2014)Approved(2014)Approved(2015)Approved(2015)Approved

199、(2017)Approved(2018)Bristol-Myers SquibbOtsuka America PharmaceuticalMerckBristol-Myers SquibbCelldex TherapeuticsNYU Langone HealthNovartisChipscreen BiosciencesBristol-Myers SquibbAgios PharmaceuticalsNumberDrugPhase of developmentCompanyList of EpiDrugsTazemetostatAbexinostatASTX727CPI-0610Entino

200、stat57Deep Pharma Intelligence1112131415Approved(2020)Phase IIIPhase IIIPhase IIIPhase IIIEpizyme,Inc.Xynomic PharmaceuticalsOtsuka America PharmaceuticalMorphoSysTaizhou EOC Pharma Co.,LtdNumberDrugPhase of developmentCompanyList of EpiDrugsGivinostatGuadecitabinePracinostatRVX-208Talazoparib161718

201、1920Phase IIIPhase IIIPhase IIIPhase IIIPhase IIIGlaxoSmithKlineOtsuka America PharmaceuticalHelsinn HealthcareResverlogixPfizerTasquinimod4SC-202ACY-1215BMS-986158DisulfiramEPZ-5676EPZ-6438GSK3326595GSK525762AINCB05432958Deep Pharma Intelligence227282930Phase IIIPhase IIPhase IIPhase IIP

202、hase IIPhase IIPhase IIPhase IIPhase IIPhase IIActive Biotech4SC Bristol-Myers SquibbBristol-Myers SquibbCantex PharmaceuticalsEpizymeEpizymeGlaxoSmithKlineGlaxoSmithKlineIncyte CorporationNumberDrugPhase of developmentCompanyList of EpiDrugsINCB057643MocetinostatORY-2001PinometostatPivanexPlitideps

203、inQuisinostatResminostatResveratrolRuxolitinib59Deep Pharma Intelligence337383940Phase IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase IIIncyte CorporationMirati Therapeutics Oryzon GenomicsNational Cancer Institute Titan PharmaceuticalsPharmaMarJanssen Research&De

204、velopment4SCGlaxoSmithKlineIncyte CorporationNumberDrugPhase of developmentList of EpiDrugsCompanySB939Valproic acidVeliparibINCB059872Olutasidenib60Deep Pharma Intelligence4142434445Phase IIPhase IIPhase IIPhase I/IIPhase I/IIS*BIOPfizerAbbottIncyte CorporationForma TherapeuticsNumberDrugPhase of d

205、evelopmentList of EpiDrugsPLX51107SeclidemstatAZD5153CHR-2845CHR-39964647484950Phase I/IIPhase I/IIPhase IPhase IPhase IPlexxikonSalarius PharmaceuticalsAstrazenecaChroma TherapeuticsChroma TherapeuticsCompanyCUDC-101EquolGSK2816126GSK2879552GSK3368715JNJ-64619178MG98OKI-179ORY-1001OTX01561Deep Phar

206、ma Intelligence557585960Phase IPhase IPhase IPhase IPhase IPhase IPhase IPhase IPhase IPhase ICurisAusio PharmaceuticalsGlaxoSmithKlineGlaxoSmithKlineGlaxoSmithKlineJanssen Research&DevelopmenNCIC Clinical Trials GroupOnKureOryzon GenomicsMerckNumberDrugPhase of developmentList of EpiDrug

207、sCompanyRO6870810TranylcypromineTrichostatin AVorasidenibGSK34362Deep Pharma Intelligence6162636465Phase IPhase IPhase IPhase IPreclinicalHoffmann-La RocheUniversity of MiamiVanda PharmaceuticalsAgios PharmaceuticalsGlaxoSmithKlineNumberDrugPhase of developmentList of EpiDrugsCompany63Deep Pharma In

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227、and transaction prospects.Competitive analysis,based on the analytical classification of companies and investors.Our Database:Our Capabilities:Visit our dashboard to learn more:www.platform.dkv.global/dashboards/ai-for-drug-discovery67Deep Pharma IntelligenceDeep Pharma Intelligence Analytical Dashb

228、oard:SWOT AnalysisAutomated SWOT analysis and benchmarking system of Deep Knowledge Group allows to replace long,resource-requiring,manual,and unsystematic process of due diligence,investment analytics,analytics insights generation and investment targeting by a real-time available product extracting

229、 insights from the largest in the world deep tech industry database with the help of deep learning algorithms and multidimensional polynomial formulas calibrated by combining expert opinions with big data analysis.This enables to conduct an investment analysis which is faster,more precise,and cheape

230、r at the same time,since it is being done automatically,permanently,without essential human interaction,and using more data points.Database,AI and ML algorithms overview6 000 000 data points which are being updated permanentlyDeep neural networks,polynomial formulas with mathematical transformations

231、,regression modelsAutomatized parsing,extrapolation using machine learning,feedback from companiesData pointsAlgorithmsData aggregationExample of the SWOT AnalysisVisit our dashboard to learn more:www.platform.dkv.global/dashboards/ai-for-drug-discoveryDeep Pharma Intelligence:Analytical Reports68De

232、ep Pharma IntelligenceArtificial Intelligence for Drug Discovery Landscape Overview,Q1 2022 is an analytical report created by Deep Pharma Intelligence company that aims to provide a comprehensive overview of the industry landscape in what pertains adoption of AI in drug discovery,clinical research

233、and other aspects of pharmaceutical R&D.Learn more:www.deep-pharma.tech/ai-in-drug-discovery-2022-q1Cancer Vaccine Industry Landscape Overview,Q1 2022 is an analytical report created by Deep Pharma Intelligence company that focuses on a segment of cancer vaccine companies.It delivers advanced market

234、 profiling,interactive mindmaps,information about companies and investors,technology application use cases and other actionable information.Learn more:https:/www.deep-pharma.tech/cancer-vaccines-q1-2022Deep Pharma Intelligence:Analytical Reports69Deep Pharma Intelligence2020 20212022Deep Pharma Inte

235、lligence(DPI)Disclaimer.The information and opinions in this report were prepared by Deep Pharma Intelligence.The information herein is believed by DPI to be reliable but DPI makes no representation as to the accuracy or completeness of such information.There is no guarantee that the views and opini

236、ons expressed in this communication will come to pass.DPI may provide,may have provided or may seek to provide advisory services to one or more companies mentioned herein.In addition,employees of DPI may have purchased or may purchase securities in one or more companies mentioned in this report.Opin

237、ions,estimates and analyses in this report constitute the current judgment of the author as of the date of this report.They do not necessarily reflect the opinions of DPI and are subject to change without notice.DPI has no obligation to update,modify or amend this report or to otherwise notify a rea

238、der thereof in the event that any matter stated herein,or any opinion,estimate,forecast or analysis set forth herein,changes or subsequently becomes inaccurate.This report is provided for informational purposes only.It is not to be construed as an offer to buy or sell or a solicitation of an offer to buy or sell any financial instruments or to participate in any particular trading strategy in any jurisdiction.E-mail:infodeep-pharma.techWebsite:www.deep-pharma.techLink to the Report:www.deep-pharma.tech/epigenetic-drugs-q2-2022