Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor

The bromodomain containing proteins
TRIM24 (tripartite motif containing
protein 24) and BRPF1 (bromodomain and PHD finger containing protein
1) are involved in the epigenetic regulation of gene expression and
have been implicated in human cancer. Overexpression of TRIM24 correlates
with poor patient prognosis, and BRPF1 is a scaffolding protein required
for the assembly of histone acetyltransferase complexes, where the
gene of MOZ (monocytic leukemia zinc finger protein) was first identified
as a recurrent fusion partner in leukemia patients (8p11 chromosomal
rearrangements). Here, we present the structure guided development
of a series of N,N-dimethyl­benzimidazolone
bromodomain inhibitors through the iterative use of X-ray cocrystal
structures. A unique binding mode enabled the design of a potent and
selective inhibitor 8i (IACS-9571) with low nanomolar
affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively).
With its excellent cellular potency (EC50 = 50 nM) and
favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of
TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.