The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, our first generation BET family bromodomain inhibitor currently under clinical development, exhibits similar affinity to each of the 8 bromodomains. It also shows potent anti-proliferative activity against a wide range of tumor cell lines. It has been hypothesized that selective inhibition of specific subsets of the BET bromodomain might provide a better therapeutic window by targeting tumor types that are predominantly driven by the gene transcriptions induced by subtype specific BET bromodomain(s). Both BDI and BDII are highly conserved across BET family members with more than 70% identity, suggesting that the generation of compounds that are selective for either the BDI or the BDII bromodomains might be achievable. Based on project team X-ray protein structures, Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) were identified as potential targets for the generation of BDII-selective inhibitors. Initial medicinal chemistry efforts resulted in a tool compound with greater than 100-fold selectivity for BRD4 BDII over BRD4 BDI. In vivo xenograft experiments demonstrated that this BDII-selective tool compound was orally efficacious in an SKM-1 AML xenograft model over a wide dose range, suggesting a potential improvement in therapeutic index. With this encouraging result, further optimization of BDII-selectivity and drug-like properties led to the identification of the clinical asset ABBV-744.

Structure based design: Identification of the clinical candidate ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor

256th National Meeting (2018)

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