Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell 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 (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. This presentation will describe further optimization of potency and PK properties in the 1,4-benzodiazepinone series that culminated in identification of BMS-986115 as a potent pan-Notch inhibitor suitable for oral dosing. Structure-activity relationships will be described along with in vivo evaluation of BMS-986115 in relevant tumor xenograft models. BMS-986115 is currently in Phase 1 clinical trials for the treatment of cancer.

Discovery of clinical candidate BMS-986115, an oral pan-Notch inhibitor for the treatment of cancer

248th National Meeting (2014)

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