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Epigenetics Probes: Production of histone modifying enzymes and identification o

Award Number: R43TR000940
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/20/2014
PERIOD OF PERFORMANCE END DATE: 06/19/2015

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Epigenetics Probes: Production of histone modifying enzymes and identification o - DESCRIPTION (provided by applicant): Production of histone modifying enzymes and identification of chemical probes for epigenetic discovery Genomic function is the major factor in the most common diseases. Genomic function is regulated by the posttranslational methylation and acetylation state of histones. Histones are proteins found in cell nuclei that create nucleosomes into which DNA is structured. Enzymes that modify histones represent important potential drug targets for indications like cancers, neurodegenerative disorders, cardiovascular, and metabolic diseases. Enzymes that catalyze these modifications include numerous histone methyltransferases and demethylases ("MT's" & "DMT's"). Additionally, proteins that recognize or "read" these histone modifications contain bromodomains, chromodomains, etc. and are also considered epigenetic factors. If medicine is to move beyond conventional drug targets that represent symptomatic treatment only, then validation of these epigenetic enzymes and factors as drug targets remains a top priority for drug discovery. Chemical epigenetic inhibitors represent a powerful opportunity here. However, histone methylation is a relatively new discovery space, and the likely structures of MT or DMT inhibitors are not yet known. Few small molecule inhibitors are available, either for laboratory research or for lead development. Therefore, there is a significant and urgent need to develop assays and to identify new chemical probes for these targets. Small molecule probes would serve a valuable role in scientific investigations and serve as medicinal chemistry scaffolds for lead development. In this proposal, we will deploy a wide-field high throughput screening (HTS) approach by testing more than 1400 privileged scaffolds that include most FDA approved drugs and clinical trial agents against over 30 histone modifying enzymes, including HMTs and histone demethylases (HDMTs). Our preliminary studies have already demonstrated very positive results by identifying and confirming hits against a handful of selected HMTs. Wide-field HTS with known orally active and relatively safe compounds offers a number of advantages for chemical probe discovery: (1) any newly identified active compound will have a known scientific pharmacology to support new applications; (2) these probes have the potential to enable "drug rescue" or "drug repurposing"; (3) for compounds already on the market, the new epigenetic activity information will help to provide enhanced understanding of their effectiveness or toxicity at the epigenetic level where no data was available; (4) for the compounds that are currently in clinical trials or have failed i late stage clinical trials, the new information will provide guidance to modify these compounds for better directed therapeutic effectiveness, and (5) this data will help establish a general chemo-epigenomic database. Having a publicly available library of epigenetic inhibitors is essential to moving ahead in this area.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2014 ( Subtotal = $287,650 )
2014	2014	REACTION BIOLOGY CORPORATION	1764 LITCHFIELD TURNPIKE, 203	WOODBRIDGE	CT	06525	SOUTH CENTRAL CT	USA	National Center for Advancing Translational Sciences	000	1	6/20/2014	NEW	$287,650
														Subtotal = $287,650

Grand Total All Awards = $287,650

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Epigenetics Probes: Production of histone modifying enzymes and identification o

Award Number: R43TR000940

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/20/2014

PERIOD OF PERFORMANCE END DATE: 06/19/2015

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