Data from Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia

• DOI: 10.1158/1535-7163.c.6543097.v1
• Publication Date: 2023-04-03T22:49:48Z
• Authors: Lu Zhang; Tianyu Cai; Xiaoyu Lin; Xiaoli Huang; Mai H. Bui; Joshua P. Plotnik; Richard J. Bellin; Emily J. Faivre; Vinitha M. Kuruvilla; Lloyd T. Lam; Xin Lu; Zheng Zha; Weiguo Feng; Paul Hessler; Tamar Uziel; Qi Zhang; Antonio Cavazos; Lina Han; Debra C. Ferguson; Gaurav Mehta; Sriram S. Shanmug...; Terrance J. Magoc; Jenny Rowe; Neal C. Goodwin; Kathleen A. Dorritie; Michael Boyiadzis; Daniel H. Albert; Keith F. McDaniel; Warren M. Kati; Marina Konopleva; Yu Shen
• Keywords: Venetoclax; BRD4

<div>Abstract<p>Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, presented dose-limiting adverse events may prevented escalation higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor four family proteins. In contrast broad antiproliferative activities observed dual inhibitors, significant largely although not exclusively cancer cell lines derived from acute myeloid leukemia androgen receptor positive prostate cancer. Studies xenograft models demonstrated antitumor efficacy was comparable pan-BET ABBV-075 but an improved therapeutic index. Enhanced also combination BCL-2 inhibitor, venetoclax compared monotherapies either agent alone. These results collectively support evaluation AML (Clinical Trials.gov identifier: NCT03360006).</p></div>