Chemical Libraries Targeting Epigenetic Methyl Writers and Erasers

PROJECT SUMMARYIn this proposalEpiCypher is partnering with DrJian Jina leader in medicinal chemistry and epigenetic
drug discoveryto develop the first epigenetics focused chemical library for histone methylationSmall molecule
inhibitors that target histone methylation are an emerging class of therapeutics for cancer treatmentThis hot
bed of drug development is fueled by the identification of numerous histone lysine methyltransferaseKMTand
demethylaseKDMenzymes that when dysregulated play driving roles in cancer initiation progressionprocesses that can be reversed upon genetic or pharmacological modulation of aberrant enzyme activityEpiCypher is pioneering the development of nucleosome based epigenetic reagents and assays to
accelerate identification of new therapeutics that target chromatin regulationNucleosomes are the repeating
units of chromatin comprised of a histone octamer andbp DNAThe use of physiological substrates is
ideal for biochemical inhibitor assays as natural substrates are more likely to identify compounds with
target specific activityFor examplethe KMT NSDa high value drug target for multiple myelomais only
active when targeting nucleosome substrates in vitro and in vivoSimilarlythe KDM A subfamily of KDMs
prefers nucleosome substrates methylated at H KTo meet this need in the marketEpiCypher is
commercializing development of recombinant nucleosomes carrying specific histone post translational
modificationsPTMstermed designer nucleosomes ordNucsfor next generation HTS assay developmentDespite our recent advances in recombinant nucleosome based assaystherapeutic development for chromatintargeting enzymes is currently limited by the lack of epigenetics focused chemical librariesIndeedcurrent
diversity libraries available today were largely engineered to target other enzyme classessuch as kinases and
GPCRsa result of historical inquiryby various companies researchersrather than targeted designFor this studywe will focus on compounds targeting histone lysine methylation regulatorsKMTs and
KDMswhich are excellent drug targets due to their strong association with cancer pathogenesisWe will employ
a unique strategy to develop novel compounds based on existing tool inhibitor scaffolds for KMT and KDM
enzymesThe resulting focused compound sets developed here will be rigorously validated using KMTs and
KDMs on EpiCypher s nucleosome based AlphaNucTM platformUsing EpiCypher s unique access to a broad
range of highly validated reagents for epigenetic enzyme assayscompounds demonstrating inhibition against
target enzymes will be tested against a panel of KMTs and KDMs to assess their specificityThis proof of concept
study is focused on histone lysine methylation due to the large number of enzymes associated with diseaseIn
Phase IIwe will vastly expand our focused compound library as well as expand to target disease relevant
arginine methyltransferases PROJECT NARRATIVEInhibition of epigenetic enzymes that target chromatin can disrupt tumor growth by slowing cancer cell
replication and promoting cell deathAs suchthere is great effort to identify chemical compounds that block the
activity of chromatin targeting enzymesparticularly those that regulate histone methylationTo date howeverchemical libraries used for drug discovery projects were largely engineered to target other enzyme classese gkinasesGPCRsa result of historical inquiryby various companies researchersrather than targeted designTo address this need in the marketEpiCypher is collaborating with DrJian Jina pioneer in epigenetic drug
discoveryto create and validate the first histone methylation focused chemical library for accelerated discovery
of precision cancer therapeutics