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Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors.

Timo Heinrich¹, Alessia Gambardella¹, Daniel Schwarz¹

¹Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.

Journal of Medicinal Chemistry

|November 10, 2025

Summary

Researchers discovered novel 5-azaindole and pyrrolo-pyridinone compounds that inhibit YAP-TEAD transcription. These inhibitors show antitumor activity in lung cancer models and potential for combination therapy.

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Area of Science:

Medicinal Chemistry
Molecular Biology
Oncology

Background:

YAP-TEAD transcriptional activity is crucial in various cancers.
Targeting YAP-TEAD is a promising strategy for cancer therapy.

Purpose of the Study:

To identify and optimize novel small molecule inhibitors of YAP-TEAD-dependent transcription.
To evaluate the in vivo efficacy of these inhibitors in lung cancer models.

Main Methods:

TEAD-reporter-based cellular screening to identify initial hits.
Structure-activity relationship studies and optimization of lead compounds.
In vivo studies using lung cancer xenograft models, including combination therapy with sotorasib.

Main Results:

A 5-azaindole hit was identified and optimized into potent pan-TEAD and TEAD-selective inhibitors.
Pyrrolo-pyridinone derivatives demonstrated improved physicochemical and pharmacokinetic properties.
Both compound classes exhibited monotherapeutic antitumor activity in lung cancer xenografts.
Synergistic antitumor effect observed when combined with a KRAS^G12C inhibitor.

Conclusions:

Novel small molecules targeting YAP-TEAD transcription have been developed.
These inhibitors show significant potential as monotherapies or in combination treatments for lung cancer.