Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• The Hippo pathway regulates organ size; its dysregulation leads to YAP/TAZ-TEAD complex hyperactivity, a hallmark of various cancers.
• Targeting YAP/TAZ-TEAD transcriptional activity presents a promising therapeutic strategy for cancer treatment.

Purpose of the Study:

• To discover and optimize small molecules that inhibit the YAP/TAZ-TEAD transcriptional activity by targeting the TEAD P-site.
• To develop an in vivo tool compound for further preclinical studies.

Main Methods:

• Structure-based drug design utilizing the X-ray structure of TEAD1.
• Fragment-based discovery and subsequent optimization of a P-site binding fragment.
• In vivo efficacy studies in mouse models and pharmacokinetic profiling.

Main Results:

• Identification and optimization of a novel TEAD P-site inhibitor, culminating in the compound MSC-4106.
• MSC-4106 demonstrated favorable potency, pharmacokinetic properties in mice, and significant in vivo efficacy.
• A time- and dose-dependent downregulation of a proximal biomarker was observed, correlating with compound exposure.

Conclusions:

• The optimized TEAD P-site inhibitor, MSC-4106, represents a viable in vivo tool for exploring YAP/TAZ-TEAD pathway inhibition in disease contexts.
• Targeting the TEAD P-site is a druggable strategy for developing novel cancer therapeutics.