Bromodomains are an important class of chromatin remodeling proteins that recognize acetylated lysine residues on histone tails. As epigenetic targets they regulate gene transcription and offer a new way to treat diseases, particularly in inflammation and oncology. The bromodomain and extra-terminal (BET) family has emerged as an important and druggable example of this class of proteins with the successful entry of small-molecule inhibitors into the clinic. Other families of bromodomains are only starting to be explored, such as the Tripartite Motif-containing 24 protein (TRIM24) and bromodomain-PHD finger protein 1 (BRPF1). Both proteins contain a dual PHD-bromo motif which have a role in recognizing specific histone marks. TRIM24 recognizes the dual histone marks of unmodified H3K4 and acetylated-H3K23 within the same histone tail. TRIM24 is a potent co-activator of ER-alpha and overexpression of TRIM24 has been linked to poor survival rates in breast cancer patients. This presentation will describe the structure guided development of a series of N,N-dimethyl-benzimidazolones through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor (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, IACS-9571 is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.

Discovery and development of a potent dual TRIM24/BRPF1 bromodomain inhibitor, IACS-9571, using structure-based drug design

251st National Meeting (2016)

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