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

Zhang, Lu; Cai, Tianyu; Lin, Xiaoyu; Huang, Xiaoli; Bui, Mai H.; Plotnik, Joshua P.; Bellin, Richard J.; Faivre, Emily J.; Kuruvilla, Vinitha M.; Lam, Lloyd T.; Lu, Xin; Zha, Zheng; Feng, Weiguo; Hessler, Paul; Uziel, Tamar; Zhang, Qi; Cavazos, Antonio; Han, Lina; Ferguson, Debra C.; Mehta, Gaurav; Shanmugavelandy, Sriram S.; Magoc, Terrance J.; Rowe, Jenny; Goodwin, Neal C.; Dorritie, Kathleen A.; Boyiadzis, Michael; Albert, Daniel H.; McDaniel, Keith F.; Kati, Warren M.; Konopleva, Marina; Shen, Yu

doi:10.1158/1535-7163.22521658.v1

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

journal contribution

posted on 2023-04-03, 18:28 authored by 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. Shanmugavelandy, 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

Supplementary figure and table legends

Funding

AbbVie

NIH

History

ARTICLE ABSTRACT

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