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
  • 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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