In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4960-4960
Abstract:
First generation BET inhibitors, including ABBV-075, bind with nearly equimolar affinity to two highly conserved bromodomains (BDI and BDII) in the N-terminus of BRD2, BRD3, BRD4, and BRDt. These “pan” inhibitors compete with the natural acetylated lysine substrates of BDI and BDII to displace BET family proteins from chromatin. In so doing, pan-BET inhibitors generally block transcription and induce potent anti-tumor activity across a wide range of pre-clinical models. Consequently, numerous phase I clinical trials have been initiated with pan-BET inhibitors. The initial reports of responses in the leading indication of AML have been encouraging; however, thrombocytopenia and other dose limiting toxicities may prevent realization of a therapeutic dose in most solid tumor indications. We hypothesized that selective inhibition of BDII but not BDI of BET family proteins would improve tolerability while retaining efficacy. Medicinal chemistry efforts produced ABBV-744, a potent inhibitor specific for BDII of BRD2/3/4, with & gt;250x differential binding preference for BDII over BDI and excellent drug-like properties. In striking contrast to the broad range of cell growth inhibition effected by pan BET inhibitor ABBV-075, BDII-selective ABBV-744 anti-proliferative activity was largely but not exclusively restricted to AML and androgen receptor (AR) positive prostate cancer cell line models, including models of Enzalutamide resistance. RNA-Seq and qPCR revealed that ABBV-744 was a potent and selective inhibitor of the AR transcription pathway. ChIP-Seq and ChIP-qPCR revealed a BDII-inhibitor displacement of BRD4 from AR-occupied enhancers and promoters, consistent with a BRD4 BDII-specific dependency of AR to sustain an oncogenic gene expression program. In vivo, doses of ABBV-744 at fractions of its MTD in LNCaP and MDA-PCa-2b xenograft models induced tumor growth inhibition that was comparable to that observed with ABBV-075 when dosed at its MTD. Together, these in vitro and in vivo results provide proof of concept that selective BDII BET family inhibitors may have improved tolerability relative to pan-BET inhibitors while maintaining tumor growth inhibition in AR positive prostate cancer. 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: Emily J. Faivre, Denise Wilcox, Mai Ha-Bui, Paul Hessler, Vasudha Sehgal, Xin Lu, Tamar Uziel, Gaurav Mehta, Daniel H. Albert, Keith McDaniel, Warren Kati, Yu Shen. First-in-class, highly BDII-selective BET family inhibitor ABBV-744 displays potent anti-tumor activity in androgen receptor positive prostate cancer models and an improved tolerability profile [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 4960.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-4960
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
