BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent

  • Bioorg Med Chem Lett. 2015 May 1;25(9):1905-9. doi: 10.1016/j.bmcl.2015.03.038.
Weifang Shan  1 ,  Aaron Balog  2 ,  Claude Quesnelle  2 ,  Patrice Gill  2 ,  Wen-Ching Han  2 ,  Derek Norris  2 ,  Sunilkumar Mandal  3 ,  Raja Thiruvenkadam  3 ,  Kiran Babu Gona  3 ,  Kamalraj Thiyagarajan  3 ,  Sathiah Kandula  3 ,  Kelly McGlinchey  2 ,  Krista Menard  2 ,  Mei-Li Wen  2 ,  Anne Rose  2 ,  Ronald White  2 ,  Victor Guarino  2 ,  Ding Ren Shen  2 ,  Mary Ellen Cvijic  2 ,  Asoka Ranasinghe  2 ,  Jun Dai  2 ,  Yingru Zhang  2 ,  Dauh-Rurng Wu  2 ,  Arvind Mathur  2 ,  Richard Rampulla  2 ,  George Trainor  2 ,  John T Hunt  2 ,  Gregory D Vite  2 ,  Richard Westhouse  2 ,  Francis Y Lee  2 ,  Ashvinikumar V Gavai  2
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States. Electronic address: [email protected].
  • 2. Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
  • 3. Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
PMID: 25857941 DOI: 10.1016/j.bmcl.2015.03.038
Abstract

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.

Keywords
Anticancer; Notch inhibitor; T-acute lymphoblastic leukemia; Triple-negative breast cancer.
Products