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

Wang, Shumei; Tsui, Vickie; Crawford, Terry D.; Audia, James E.; Burdick, Daniel J.; Beresini, Maureen H.; Côté, Alexandre; Cummings, Richard; Duplessis, Martin; Flynn, E. Megan; Hewitt, Michael C.; Huang, Hon-Ren; Jayaram, Hariharan; Jiang, Ying; Joshi, Shivangi; Murray, Jeremy; Nasveschuk, Christopher G.; Pardo, Eneida; Poy, Florence; Romero, F. Anthony; Tang, Yong; Taylor, Alexander M.; Wang, Jian; Xu, Zhaowu; Zawadzke, Laura E.; Zhu, Xiaoyu; Albrecht, Brian K.; Magnuson, Steven R.; Bellon, Steve; Cochran, Andrea G.

doi:10.1021/acs.jmedchem.8b01225.s002

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

journal contribution

posted on 2018-10-04, 20:43 authored by Shumei Wang, Vickie Tsui, Terry D. Crawford, James E. Audia, Daniel J. Burdick, Maureen H. Beresini, Alexandre Côté, Richard Cummings, Martin Duplessis, E. Megan Flynn, Michael C. Hewitt, Hon-Ren Huang, Hariharan Jayaram, Ying Jiang, Shivangi Joshi, Jeremy Murray, Christopher G. Nasveschuk, Eneida Pardo, Florence Poy, F. Anthony Romero, Yong Tang, Alexander M. Taylor, Jian Wang, Zhaowu Xu, Laura E. Zawadzke, Xiaoyu Zhu, Brian K. Albrecht, Steven R. Magnuson, Steve Bellon, Andrea G. Cochran

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.