Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Probe Development for Histone Demethylase Networks

Award Number: R43DA042684
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2017

Group Awards By:

View Award Description

Probe Development for Histone Demethylase Networks - ¿ DESCRIPTION (provided by applicant): Lysine demethylases (KDMs) catalyze the removal of methyl groups from the side-chain amino groups of tri-, di- and mono-methylysines (Kme3/2/1), notably at specific sites in the N-terminal 'tails' of histones. There are two groups of KDMs: 1) the lysine-specific demethylases (LSDs 1 and 2), flavin dependent amine oxidases that can demethylate Kme2/1 and 2) the JmjC-domain-containing oxidases, Fe2+ and a-ketoglutarate requiring enzymes that, in many cases, can also demethylate Kme3. Histone lysine methylations are epigenetic regulatory modifications that profoundly affect gene expression and aberrant histone lysine methylation occurs in a number of diseases including cancer. Excess activity of a number of particular KDMs is implicated in a variety of cancers. Interest in the discovery of drugs that inhibit KDMs is therefore growing but, especially for the JmjC enzymes, which is the largest of the two groups of KDMs. A factor which is slowing progress toward eventual development of drugs that target the JmjC KDMs is a lack of chemical probes, with probes defined as highly potent and highly specific inhibitors of individual JmjC KDMs. One circumstance that may be contributing to the lack of specific probes is that the existing inhibitor exclusively target the highly conserved binding site of the co-substrate, 2-oxoglutarate (2-OG) and/or chelate the active site Fe2+. In order to provide tools that may help remedy this situation, we are proposing to produce a comprehensive collection of JmjC KDM proteins, which will include full-length proteins, catalytic domain (demethylase) constructs and separate individual constructs for each of the many 'reader' domains (e.g. PHD or double Tudor domains) that form part of most, but not all, full-length JmjC KDMs. Once these proteins are in hand, we will develop at least one assay (binding or demethylation) and begin by screening all of them against a collection of FDA-approved drugs and compounds from clinical trials. The chemical profiles of the demethylase and reader domains thus generated will be incorporated in a database and made publicly available as a general aid to research in this area. The proteins that are produced in the process will become available as products and the assays that are developed will become services that we offer. Finally, these proteins will be screened against a much larger chemically diverse library (>80,000 compounds). Inhibitors that are identified will also become products. In Phase II we envision that some of these inhibitors will be used as the starting point for chemistry to produce more potent probes or to produce fluorophor-labeled probes for fluorescence polarization assays.


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: 2018 ( Subtotal = $0 )
2018	2016	REACTION BIOLOGY CORPORATION	1 GREAT VALLEY PKWY STE 2	MALVERN	PA	19355	CHESTER	USA	Drug Use and Addiction Research Programs	000	1	1/9/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $247,791 )
2016	2016	REACTION BIOLOGY CORPORATION	1764 LITCHFIELD TURNPIKE, 203	WOODBRIDGE	CT	06525	SOUTH CENTRAL CT	USA	Drug Use and Addiction Research Programs	000	1	3/14/2016	NEW	$247,791
														Subtotal = $247,791

Grand Total All Awards = $247,791

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Probe Development for Histone Demethylase Networks

Award Number: R43DA042684

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2017

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer