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

Shan, Weifang; Balog, Aaron; Quesnelle, Claude; Gill, Patrice; Han, Wen-Ching; Norris, Derek; Mandal, Sunilkumar; Thiruvenkadam, Raja; Gona, Kiran Babu; Thiyagarajan, Kamalraj; Kandula, Sathiah; McGlinchey, Kelly; Menard, Krista; Wen, Mei-Li; Rose, Anne; White, Ronald; Guarino, Victor; Shen, Ding Ren; Cvijic, Mary Ellen; Ranasinghe, Asoka; Dai, Jun; Zhang, Yingru; Wu, Dauh-Rurng; Mathur, Arvind; Rampulla, Richard; Trainor, George; Hunt, John T; Vite, Gregory D; Westhouse, Richard; Lee, Francis Y; Gavai, Ashvinikumar V.

Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.

Article in English | MEDLINE | ID: mdl-25857941

ABSTRACT

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of Î³-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.

Subject(s)

Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzodiazepinones/administration & dosage , Benzodiazepinones/pharmacology , Receptors, Notch/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Benzodiazepinones/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Receptors, Notch/metabolism , Structure-Activity Relationship

ABSTRACT

Subject(s)

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