2. Academic Validation
  3. GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1

GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1

  • J Med Chem. 2022 Aug 25;65(16):11177-11186. doi: 10.1021/acs.jmedchem.2c00662.
Alexander M Taylor 1,  Chris Bailey 1,  Lisa D Belmont 2,  Robert Campbell 1,  Nico Cantone 1,  Alexandre Côté 1,  Terry D Crawford 2,  Richard Cummings 1,  Kevin DeMent 2,  Martin Duplessis 1,  Megan Flynn 2,  Andrew C Good 1,  Hon-Ren Huang 1,  Shivangi Joshi 1,  Yves Leblanc 1,  Jeremy Murray 2,  Christopher G Nasveschuk 1,  Adrianne Neiss 1,  Florence Poy 1,  F Anthony Romero 2,  Peter Sandy 1,  Yong Tang 1,  Vickie Tsui 2,  Laura Zawadzke 1,  Robert J Sims 3rd 1,  James E Audia 1,  Steven F Bellon 1,  Steven R Magnuson 2,  Brian K Albrecht 1,  Andrea G Cochran 2
Affiliations

Affiliations

  • 1 Constellation, a Morphosys Company, 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
  • 2 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 35930799 DOI: 10.1021/acs.jmedchem.2c00662
Abstract

Bromodomains are acetyllysine recognition domains present in a variety of human proteins. Bromodomains also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highly potent and selective ligands with good cellular permeability have been proposed as chemical probes for use in exploring the functions of many of the bromodomain proteins. We report here the discovery of a class of such inhibitors targeting the family VIII bromodomains of SMARCA2 (BRM) and SMARCA4 (BRG1), and PBRM1 (polybromo-1) bromodomain 5. We propose one example from this series, GNE-064, as a chemical probe for the bromodomains SMARCA2, SMARCA4, and PBRM1(5) with the potential for in vivo use.

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