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Accelerated discovery of methylation targeted therapeutic development

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43CA212733-01
Agency Tracking Number: R43CA212733
Amount: $224,214.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 102
Solicitation Number: PA15-269
Solicitation Year: 2016
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-09-16
Award End Date (Contract End Date): 2017-05-31
Small Business Information
Chapel Hill, NC 27514-4617
United States
DUNS: 078882699
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 843-3935
Business Contact
Phone: (919) 923-3716
Research Institution

Project Summary
Nucleosomes are the fundamental and repeating units of chromatin consisting of DNA wrapped around
a histone octamer Alterations in chromatin structure and function dramatically impact downstream gene
expression and cellular physiology This epigenetic regulation is controlled by two major modifications histone
post translational modifications PTMs such as histone methylation acetylation and ubiquitination and DNA
methylation Significantly specific alterations in the epigenetic landscape are associated with a diverse array of
human diseases most notable of which are cancers Understanding this so called histone code is essential
for developing targeted therapies that manipulate or alter epigenetic signaling to treat human disease As a key
step toward deciphering the histone code EpiCypher Inc has initiated a robust research program to develop
recombinant nucleosome based reagents and assays which capitalize on physiological properties of
chromatin architecture Recent studies show that histone and DNA methylation signaling pathways are
interdependent and may synergistically alter the activity of chromatin modifying enzymes These data not only
support the hypothesis that histone and DNA methylation dependent signaling are mechanistically linked but
provide a unique opportunity for novel drug discovery Currently there are no commercially available research
tools to biochemically profile the interplay between specific histone PTMs and DNA methylation on a single
assay substrate Here we will develop an innovative nucleosome based assay platform engineered to
leverage the crosstalk between histone PTMs DNA methylation and chromatin interacting modifying enzymes
to accelerate drug discovery In Phase I we will develop methods to generate recombinant nucleosomes
carrying unique DNA and histone methylation profiles Using these reagents as biochemical substrates we will
demonstrate feasibility that this assay platform will be useful for drug discovery by establishing novel effector
binding and enzymatic assays using proteins known to interact with DNA and or histone methylation such as
UHRF UHRF is an E ubiquitin protein ligase whose activity is greatly enhanced in the presence of
hemimethylated DNA and histone H K me Significantly UHRF overactivation is associated with bladder
and colon cancer In Phase we will continue to optimize the commercial synthesis of designer nucleosomes
assembled using methylated DNA templates which we will use to develop additional novel effector binding and
enzymatic assays These reagents and assays will be assembled into a series of stand alone kits for
innovative drug discovery In addition we will develop a designer nucleosome based UHRF inhibitor screen
that leverages the molecular interactions between UHRF and DNA histone methylation to identify context
specific inhibitors of UHRF for cancer therapeutic development The breakthrough technology developed here
is greatly needed by the epigenetic research community and will enable the identification of novel drug targets
as well as the development of precision therapeutics
Project Narrative
Histone and DNA methylation signaling pathways are interdependent and may synergistically alter the
activity of chromatin modifying enzymes However disease relevant interactions between these major
epigenetic signaling pathways are difficult to study using currently available research tools Here EpiCypher
will develop an innovative recombinant nucleosome based drug discovery platform that leverages interactions
between histone and DNA methylation on a single assay substrate The innovative assay platform developed
herein will enable the discovery of novel drug targets as well as prove useful in the identification of context
specific inhibitors for targeted cancer therapy

* Information listed above is at the time of submission. *

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