Q1 · MEDICINE
Article
Author: Jayaram, Hariharan ; Murray, Jeremy ; Romero, F. Anthony ; Joshi, Shivangi ; Hewitt, Michael C. ; Jiang, Ying ; Pardo, Eneida ; Cochran, Andrea G. ; Duplessis, Martin ; Bellon, Steve ; Poy, Florence ; Zawadzke, Laura E. ; Tang, Yong ; Beresini, Maureen H. ; Cummings, Richard ; Crawford, Terry D. ; Xu, Zhaowu ; Taylor, Alexander M. ; Zhu, Xiaoyu ; Nasveschuk, Christopher G. ; Burdick, Daniel J. ; Audia, James E. ; Wang, Jian ; Flynn, E. Megan ; Huang, Hon-Ren ; Albrecht, Brian K. ; Magnuson, Steven R. ; Cote, Alexandre ; Tsui, Vickie ; Wang, Shumei
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.