Bms-983970, An Oral Pan-Notch Inhibitor For The Treatment Of Cancer

Abstract Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. γ-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. Based on the preclinical data, the projected human half-life of BMS-906024 is in the 37 h - 124 h range. This presentation will describe further structure-activity relationships in the 1,4-benzodiazepinone series that culminated in the identification of BMS-983970 as an oral-pan-Notch inhibitor. Pharmacokinetic properties and in vivo evaluation of BMS-983970 in T-ALL and solid tumor xenograft models will be presented. Citation Format: Ashvinikumar V. Gavai, Yufen Zhao, Daniel O'Malley, Brian Fink, Claude Quesnelle, Derek Norris, Libing Chen, Soong-Hoon Kim, Wen-Ching Han, Patrice Gill, Weifang Shan, Aaron Balog, Andrew Tebben, Richard Rampulla, Dauh-Rurng Wu, Yingru Zhang, Arvind Mathur, Haiqing Wang, Zheng Yang, Qian Ruan, Robin Moore, David Rodrigues, Asoka Ranasinghe, Celia D'Arienzo, Ching Kim Tye, Ching Su, Gerry Everlof, Melissa Yarde, Mary Ellen Cvijic, Krista Menard, Mei-Li Wen, George Trainor, Bruce Fischer, John Hunt, Gregory Vite, Richard Westhouse, Francis Lee. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2014-1643