MSC-4106 (C09-1152-543)

MSC-4106 is an orally active and potent inhibitor of YAP/TAZ-TEAD . MSC-4106 inhibits TEAD1 or TEAD3 auto-palmitoylation and shows inhibitory effect on NCI-H226 tumor xenograft modelIn VitroMSC-4106 (10 μM, 24 h) inhibited SK-HEP-1 reporter and NCI-266 cell viability with IC 50 values of 4 nM and 14 nM, respectively. MSC-4106 (10 μM, 6 h) crystallizes in the P-site of TEAD1, and against TEAD1 or TEAD3 palmitoylation in TEAD-Overexpressing HEK293 Cells by 97.3% and 75.9%, respectively. MSC-4106 (10 μM, 4 d) targets TEAD indicated by a reduction in viability of NCI-H226 cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: NCI-H226 (YAP dependent); SW620 YAP/TAZ KO (Yap-independent) cells Concentration: 0, 3, 6, 9, 12, 15, 18, 21, 24, 26, 30 μM Incubation Time: 96 hours Result: Showed inhibitory effect to NCI-H226 and general cytotoxic to SW620 (IC 50 >30 μM). ImmunofluorescenceCell Line: SK-HEP-1 Concentration: 0, 3, 6, 9, 12, 15, 18, 21, 24, 26, 30 μM Incubation Time: 24 hours Result: Inhibited YAP-TEAD interation.In VivoMSC-4106 (100 mg/kg/d; p.o.; 7 d) displays anti-tumor effect with controlled tumor volume and good tolerability with stable body weight in mice . MSC-4106 (1, 5, 100 mg/kg/d; p.o.; 0-72 h) down-regulates Cyr61 (cysteine-rich angiogenic inducer 61) expression, the TEAD-regulated target gene, in tumor lysates at all time points at 100 mg/kg and 24 h at 5 mg/kg . Pharmacokinetics (PK) profile in different species Parameter Mouse Rat Dog Cl (l/h/kg) 0.2 0.7 0.05 PO t 1/2 (h) 45 40 3.6 PO AUC (μg•h/mL) 45 10 33 V ss (L/kg) 2 5 0.3 F (%) >90 80 18 Note : PO studies were performed at 10 mg/kg ; MSC-4106 was formulated in 20% Kleptose in 50 mM PBS at pH 7.4. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: NCI-H226 xenograft model in H2d Rag2 female mice (9-week-old) Dosage: 5, 100 mg/kg Administration: Oral gavage; once daily; 32 days Result: Resulted tumor growth controlled with 5 mg/kg while regressed with 100 mg/kg dosing after 32 treatment days.Form:SolidIC50& Target:Target: YAP. Specifications and Purity: 99%. Molecular Formula: C18H12F3N3O2. Molecular Weight: 359.30.