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00085472can161793-sup-168446_2_supp_3932120_mnm2kj.pptx (105.73 kB)

Supplemental figure 1 from Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies

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posted on 2023-03-31, 00:45 authored by Mai H. Bui, Xiaoyu Lin, Daniel H. Albert, Leiming Li, Lloyd T. Lam, Emily J. Faivre, Scott E. Warder, Xiaoli Huang, Denise Wilcox, Cherrie K. Donawho, George S. Sheppard, Le Wang, Steve Fidanze, John K. Pratt, Dachun Liu, Lisa Hasvold, Tamar Uziel, Xin Lu, Fred Kohlhapp, Guowei Fang, Steven W. Elmore, Saul H. Rosenberg, Keith F. McDaniel, Warren M. Kati, Yu Shen

BRD4 binding to Myc regulatory region

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ARTICLE ABSTRACT

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976–89. ©2017 AACR.

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