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Published on: March 3, 2021
Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106
Timo Heinrich1, Carl Peterson1, Richard Schneider1
1Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Abstract:
The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.
Insights
Researchers developed a new drug, MSC-4106, targeting the YAP/TAZ-TEAD complex to treat cancers linked to the Hippo pathway. This P-site inhibitor shows promising in vivo efficacy and biomarker modulation.
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.
