MSC-4106, an orally active and potent YAP/TAZ-TEAD inhibitor, disrupts TEAD1 and TEAD3 auto-palmitoylation and demonstrates significant efficacy in the NCI-H226 tumor xenograft model [1].

MSC-4106, at a concentration of 10 μM, demonstrated notable effects in various assays related to cancer cell viability and interaction inhibition within a certain time frame. Specifically, after 24 hours of treatment, it significantly reduced the viability of SK-HEP-1 reporter and NCI-266 cells, with IC50 values measuring at 4 nM and 14 nM, respectively. Additionally, within 6 hours, it was observed to crystalize in the P-site of TEAD1, markedly inhibiting TEAD1 and TEAD3 palmitoylation in TEAD-overexpressing HEK293 cells by 97.3% and 75.9%, correspondingly. A four-day exposure to MSC-4106 also suggested its targeting action on TEAD through a diminished viability in NCI-H226 cells, indicative of its potential mechanistic pathways. Further evaluation via a Cell Viability Assay on NCI-H226 (YAP dependent) and SW620 YAP/TAZ KO (YAP-independent) cells exposed to varying concentrations of MSC-4106 for 96 hours revealed an inhibitory effect on NCI-H226 and a general cytotoxicity towards SW620 with an IC50 greater than 30 μM. Immunofluorescence studies in SK-HEP-1 cells after 24 hours of treatment confirmed the inhibition of YAP-TEAD interaction, showcasing MSC-4106’s multifaceted biochemical activities.

MSC-4106 (P.O.; 100 mg/kg once daily; 7 days) demonstrates anti-tumor effects with controlled tumor volume and good tolerability, maintaining stable body weight in mice [1]. MSC-4106 (P.O.; 1, 5, 100 mg/kg once daily; 6, 24, 30, 48, and 72 h) down-regulates Cyr61 (cysteine-rich angiogenic inducer 61) expression, a TEAD-regulated target gene, in tumor lysates at all time points at 100 mg/kg and at 24 h at 5 mg/kg [1]. Pharmacokinetic (PK) profiles in different species [1]:

- Mouse: Cl (0.2 l/h/kg), PO t 1/2 (45 h), PO AUC (45 μg h/mL), V ss (2 L/kg), F (>90%).
- Rat: Cl (0.7 l/h/kg), PO t 1/2 (40 h), PO AUC (10 μg h/mL), V ss (5 L/kg), F (80%).
- Dog: Cl (0.05 l/h/kg), PO t 1/2 (3.6 h), PO AUC (33 μg h/mL), V ss (0.3 L/kg), F (18%).

Note: PO studies at 10 mg/kg; MSC-4106 formulated in 20% Kleptose in 50 mM PBS, pH 7.4. Animal model: NCI-H226 xenograft in H2d Rag2 female mice (9-week-old) [1]. Dosage: 5, 100 mg/kg Oral gavage, once daily for 32 days, resulting in controlled tumor growth at 5 mg/kg and tumor regression at 100 mg/kg after 32 days of treatment.