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 model[1].
MSC-4106 (10 μM, 24 h) inhibited SK-HEP-1 reporter and NCI-266 cell viability with IC50 values of 4 nM and 14 nM, respectively[1].
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[1].
MSC-4106 (10 μM, 4 d) targets TEAD indicated by a reduction in viability of NCI-H226 cells[1].
Cell Viability Assay[1]
| Cell 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 (IC50 >30 μM). |
Immunofluorescence[1]
| Cell 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. |
MSC-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[1].
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[1].
Pharmacokinetics (PK) profile in different species[1]
| Parameter | Mouse | Rat | Dog |
| Cl (l/h/kg) | 0.2 | 0.7 | 0.05 |
| PO t1/2 (h) | 45 | 40 | 3.6 |
| PO AUC (μg•h/mL) | 45 | 10 | 33 |
| Vss (L/kg) | 2 | 5 | 0.3 |
| F (%) | >90 | 80 | 18 |
| Animal Model: | NCI-H226 xenograft model in H2d Rag2 female mice (9-week-old)[1] |
| 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. |