Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors

  • ACS Med Chem Lett. 2015 Mar 11;6(5):523-7. doi: 10.1021/acsmedchemlett.5b00001.
Ashvinikumar V Gavai  1 ,  Claude Quesnelle  1 ,  Derek Norris  1 ,  Wen-Ching Han  1 ,  Patrice Gill  1 ,  Weifang Shan  1 ,  Aaron Balog  1 ,  Ke Chen  2 ,  Andrew Tebben  1 ,  Richard Rampulla  1 ,  Dauh-Rurng Wu  1 ,  Yingru Zhang  1 ,  Arvind Mathur  1 ,  Ronald White  1 ,  Anne Rose  1 ,  Haiqing Wang  1 ,  Zheng Yang  1 ,  Asoka Ranasinghe  1 ,  Celia D'Arienzo  1 ,  Victor Guarino  1 ,  Lan Xiao  1 ,  Ching Su  1 ,  Gerry Everlof  1 ,  Vinod Arora  3 ,  Ding Ren Shen  1 ,  Mary Ellen Cvijic  1 ,  Krista Menard  1 ,  Mei-Li Wen  1 ,  Jere Meredith  3 ,  George Trainor  1 ,  Louis J Lombardo  1 ,  Richard Olson  3 ,  Phil S Baran  2 ,  John T Hunt  1 ,  Gregory D Vite  1 ,  Bruce S Fischer  1 ,  Richard A Westhouse  1 ,  Francis Y Lee  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543, United States.
  • 2. Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
  • 3. Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
PMID: 26005526 DOI: 10.1021/acsmedchemlett.5b00001
Abstract

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Keywords
Notch inhibitor; SAR; T-acute lymphoblastic leukemia; triple-negative breast cancer; γ-secretase inhibitor.
Products