title: BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent.
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.
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States. Electronic address: weifang.shan@bms.com.
authors: Weifang
authors: W
authors: Shan
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Aaron
authors: A
authors: Balog
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Claude
authors: C
authors: Quesnelle
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Patrice
authors: P
authors: Gill
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Wen-Ching
authors: WC
authors: Han
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Derek
authors: D
authors: Norris
authors: Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors: Sunilkumar
authors: S
authors: Mandal
authors: Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors: Raja
authors: R
authors: Thiruvenkadam
authors: Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors: Kiran Babu
authors: KB
authors: Gona
authors: Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors: Kamalraj
authors: K
authors: Thiyagarajan
authors: Biocon BMS Research and Development Center (BBRC), Syngene International Ltd, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors: Sathiah
authors: S
authors: Kandula
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Kelly
authors: K
authors: McGlinchey
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Krista
authors: K
authors: Menard
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Mei-Li
authors: ML
authors: Wen
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Anne
authors: A
authors: Rose
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Ronald
authors: R
authors: White
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Victor
authors: V
authors: Guarino
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Ding Ren
authors: DR
authors: Shen
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Mary Ellen
authors: ME
authors: Cvijic
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Asoka
authors: A
authors: Ranasinghe
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Jun
authors: J
authors: Dai
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Yingru
authors: Y
authors: Zhang
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Dauh-Rurng
authors: DR
authors: Wu
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Arvind
authors: A
authors: Mathur
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Richard
authors: R
authors: Rampulla
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: George
authors: G
authors: Trainor
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: John T
authors: JT
authors: Hunt
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Gregory D
authors: GD
authors: Vite
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Richard
authors: R
authors: Westhouse
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Francis Y
authors: FY
authors: Lee
authors: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States.
authors: Ashvinikumar V
authors: AV
authors: Gavai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C000604995:BMS-871; D001570:Benzodiazepinones; D051880:Receptors, Notch
keywords: Anticancer; Notch inhibitor; T-acute lymphoblastic leukemia; Triple-negative breast cancer