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][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03360006&atom=%2Fmolcanther%2F20%2F10%2F1809.atom

中文翻译：

---

选择性抑制 BET 家族蛋白第二溴结构域在急性髓系白血病临床前模型中产生强大的抗肿瘤活性


双溴结构域 BET 抑制剂与 BRD2、BRD3、BRD4 和 BRDT 中的第一和第二溴结构域具有相似的亲和力，在临床试验中作为单一疗法表现出适度的活性。血小板减少症，紧随其后的是胃肠道毒性症状，已表现为剂量限制性不良事件，可能阻止升级至更强大疗效所需的更高剂量水平。 ABBV-744 是四种 BET 家族蛋白第二个溴结构域的高度选择性抑制剂。与双溴结构域 BET 抑制剂观察到的广泛抗增殖活性相反，ABBV-744 在源自急性髓系白血病和雄激素受体阳性前列腺癌的癌细胞系中表现出显着的抗增殖活性，尽管不完全如此。急性髓系白血病异种移植模型的研究表明，ABBV-744 的抗肿瘤功效与泛 BET 抑制剂 ABBV-075 相当，但治疗指数有所提高。与单独使用任一药物的单一疗法相比，ABBV-744 和 BCL-2 抑制剂 Venetoclax 的组合也观察到增强的抗肿瘤功效。这些结果共同支持 ABBV-744 在 AML 中的临床评估（Clinical Trials.gov 标识符：[NCT03360006][1]）。 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03360006&atom=%2Fmolcanther%2F20%2F10%2F1809.atom