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

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.