2. Academic Validation
  3. GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like

GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like

  • J Med Chem. 2018 Oct 25;61(20):9301-9315. doi: 10.1021/acs.jmedchem.8b01225.
Shumei Wang 1,  Vickie Tsui 1,  Terry D Crawford 1,  James E Audia 2,  Daniel J Burdick 1,  Maureen H Beresini 1,  Alexandre Côté,  Richard Cummings 2,  Martin Duplessis 2,  E Megan Flynn 1,  Michael C Hewitt 2,  Hon-Ren Huang 2,  Hariharan Jayaram 2,  Ying Jiang 3,  Shivangi Joshi 2,  Jeremy Murray 1,  Christopher G Nasveschuk 2,  Eneida Pardo 2,  Florence Poy 2,  F Anthony Romero 1,  Yong Tang 2,  Alexander M Taylor 2,  Jian Wang 3,  Zhaowu Xu 3,  Laura E Zawadzke 2,  Xiaoyu Zhu 3,  Brian K Albrecht 2,  Steven R Magnuson 1,  Steve Bellon 2,  Andrea G Cochran 1
Affiliations

Affiliations

  • 1 Genentech Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 2 Constellation Pharmaceuticals , 215 First Street, Suite 200 , Cambridge , Massachusetts 02142 , United States.
  • 3 Wuxi Apptec Company, Ltd. , 288 Fute Zhong Road , Waigaoqiao Free Trade Zone, Shanghai 200131 , People's Republic of China.
PMID: 30289257 DOI: 10.1021/acs.jmedchem.8b01225
Abstract

The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.

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