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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzodiazepinones / administration & dosage*
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Benzodiazepinones / chemistry
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Benzodiazepinones / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Humans
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Receptors, Notch / antagonists & inhibitors*
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Receptors, Notch / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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BMS-871
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Benzodiazepinones
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Receptors, Notch