CNS penetrant TEAD1,2,4 inhibitor MSC-4070 derived from phenotypic screening hit optimization

TEAD proteins are attractive cancer targets due to their role in cell proliferation and metastasis. We report the development of MSC-4070, a CNS-penetrant TEAD1,2,4 inhibitor derived from phenotypic screening hit optimization. Starting with azaindole and lactam scaffolds, we systematically designed compounds to enhance brain penetration while maintaining target potency. Analysis of molecular properties revealed that <i>N</i>-methylation significantly reduced efflux ratios in Caco-2 and MDCK-MDR1 assays without compromising activity. MSC-4070 exhibited favorable pharmacokinetics with brain-to-plasma ratios of 2.5-4 and <i>K</i> _{p_{u, u}} values of 0.5-1, confirming its CNS penetration. This compound demonstrated potent activity in the TEAD reporter assay (IC₅₀ 14 nM) and cell viability assays (IC₅₀ 30-149 nM), with selectivity for TEAD1,2,4 over TEAD3. Our findings indicate that while molecular weight and TPSA influence CNS penetration, efflux transporter interactions are more predictive of brain exposure. MSC-4070 represents a promising candidate for targeting TEAD-driven tumors in the central nervous system.