Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including breast cancer, lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. Gamma-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. This presentation will summarize structure-activity relationship in a series of inhibitors of gamma-secretase mediated Notch signaling that culminated in identification of BMS-906024 as the clinical candidate. In vivo evaluation of the clinical candidate will be described in relevant tumor xenograft models. BMS-906024 is currently in Phase I clinical trials for the treatment of cancer.

Discovery and preclinical pharmacology of BMS-906024, a pan-Notch inhibitor for the treatment of cancer

245th National Meeting (2013)

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