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

Area of Science:

• Oncology
• Medicinal Chemistry
• Neuroscience

Background:

• TEAD proteins are key drivers of cancer cell proliferation and metastasis.
• Targeting TEAD proteins presents a promising strategy for cancer therapy.
• Developing CNS-penetrant inhibitors is crucial for treating brain tumors.

Purpose of the Study:

• To develop a novel, CNS-penetrant TEAD inhibitor for potential treatment of central nervous system (CNS) tumors.
• To optimize compounds for enhanced brain penetration while maintaining target potency.
• To investigate the relationship between molecular properties and CNS penetration.

Main Methods:

• Systematic design and synthesis of compounds based on azaindole and lactam scaffolds.
• Evaluation of brain penetration using Caco-2 and MDCK-MDR1 efflux assays.
• Pharmacokinetic studies to determine brain-to-plasma ratios and K_p,uu values.
• Assessment of TEAD reporter assay and cell viability inhibition.

Main Results:

• MSC-4070 demonstrated significant CNS penetration with favorable pharmacokinetic properties.
• N-methylation was identified as a strategy to reduce efflux without compromising target activity.
• MSC-4070 showed potent inhibition of TEAD1,2,4 (IC50 14 nM) and cancer cell viability (IC50 30-149 nM).
• Efflux transporter interactions were found to be more predictive of brain exposure than molecular weight or TPSA.

Conclusions:

• MSC-4070 is a potent and CNS-penetrant TEAD inhibitor.
• The study highlights the importance of efflux transporter interactions in designing brain-penetrant drugs.
• MSC-4070 is a promising candidate for targeting TEAD-driven CNS tumors.