Abstract DDT01-05: ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor

Abstract

Abstract 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, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. The BDII bromdomains are highly conserved across BET family members (>70% identity), suggesting that the generation of compounds that are selective for the four BDII bromodomains relative to the four BDI bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) helped to guide the identification of structural analogs of ABBV-075 demonstrating greater than 300X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration ultimately resulted in the discovery of BDII-selective compounds with improved oral bioavailability and the identification of the clinical asset ABBV-744. In striking contrast to the broad range of cell growth inhibition effected by pan BET inhibitor ABBV-075, the anti-proliferative activity for BDII-selective ABBV-744 was largely but not exclusively restricted to AML and androgen receptor (AR) positive prostate cancer cell line models, including models of Enzalutamide resistance. In vivo, doses of ABBV-744 at fractions of its MTD induced tumor growth inhibition in AML and prostate cancer xenograft models that were comparable to those observed with ABBV-075 when dosed at its MTD. Together, these in vitro and in vivo results provide proof of concept that highly selective BDII BET family bromodomain inhibitors may have improved tolerability relative to pan-BET inhibitors while maintaining tumor growth inhibition in AML and AR positive prostate cancer. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Warren Kati. ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT01-05.