BMS-906024

BMS-906024 is an orally active and selective γ-secretase (gamma secretase) inhibitor. BMS-906024 is a potent pan- Notch receptors inhibitor with IC 50 s of 1.6 nM, 0.7 nM, 3.4 nM, and 2.9 nM for Notch1, -2, -3, and -4 receptors, respectively. BMS-906024 demonstrates broad-spectrum antineoplastic activity In Vitro BMS-906024 (5-100 nM; 72 hours) reduces Notch1 ICD levels in all six lung cancer cell lines. BMS-906024 at 100 nM, has no effect on total Notch1, and down-regulated Hes1 transcript. In cancer cell proliferation assays, BMS-906024 inhibits both leukemia (TALL-1) and triple-negative breast cancer (MDA-MB-468) cells with IC 50 of ∼4 nM. BMS-906024 (100 nM; for 72 hours) enhances the anti-tumor activity of Paclitaxel in vitro. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: NSCLC cell lines (A549, H358, H1975, H2444, H1792, HCC44) Concentration: 5, 10, 25, 50, 100 nM Incubation Time: 72 hours Result: Reduced Notch1 ICD levels in all six lung cancer cell lines tested at concentrations as low as 5 nM, with maximal depletion at 50-100 nM. In Vivo BMS-906024 (8.5 mg/kg; oral gavage; days 1 through 4 of each week for 3 weeks) significantly enhances the tumor growth inhibition of Paclitaxel (36 mg/kg). BMS-906024 enhances Paclitaxel-mediated cytotoxicity in vivo in NSCLC through a combination of inhibiting proliferation and promoting apoptosis, in a p21 and p57-independent manner . BMS-906024 has a T 1/2 of 4.6/5.3 hours, a C max of 1/0.3 μM and an AUC of 3.4/1.9 μM•hour for IV/PO. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Six to 12-week-old female NOD scid gamma (NSG) mice with KRAS- and BRAF-WT PDX-T42 xenografts Dosage: 8.5 mg/kg Administration: oral gavage; days 1 through 4 of each week for 3 weeks Result: Significantly enhanced the tumor growth inhibition of Paclitaxel (36 mg/kg), but had no significant effect on Cisplatin (2 mg/kg) treatment. Animal Model: MouseDosage: 1 mg/kg (Pharmacokinetic Analysis) Administration: IV or PO Result: Had a T 1/2 of 4.6/5.3 hours, a C max of 1/0.3 μM and an AUC of 3.4/1.9 μM•hour for IV/PO. Form:Solid IC50& Target:IC50: 1.6 nM (Notch1), 0.7 nM (Notch2), 3.4 nM (Notch3) and 2.9 nM (Notch4)

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