In Vitro: 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. 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.
In Vivo: 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. 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 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
Note: PO studies were performed at 10 mg/kg; MSC-4106 was formulated in 20% Kleptose in 50 mM PBS at pH 7.4.