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
posted on 2018-10-04, 20:43authored byShumei 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.