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Phase separation-based HTS identifies cobimetinib as a YAP-TEAD inhibitor that suppresses hyperactivated YAP-induced

Ruizeng Yang1,2, Liqiao Hu3,4, Jing Wang5

  • 1Department of Urology, Shanghai Sixth People' s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai 200233, China.

Science Translational Medicine
|April 22, 2026
PubMed

Insights

Cobimetinib inhibits the YAP-TEAD complex, a key driver of cancer. This FDA-approved drug shows promise in overcoming treatment resistance and suppressing tumor growth in lung and liver cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The Hippo signaling pathway regulates cell growth and organ size.
  • Dysregulation of this pathway, particularly the YAP-TEAD complex, is linked to various cancers.
  • Targeting the YAP-TEAD complex offers therapeutic potential for cancer treatment.

Purpose of the Study:

  • To develop a high-throughput screening assay for YAP-TEAD complex inhibitors.
  • To identify existing drugs that can inhibit the YAP-TEAD complex.
  • To evaluate the efficacy of identified inhibitors in preclinical cancer models.

Main Methods:

  • Developed a high-throughput screening (HTS) assay using phase separation principles.
  • Utilized cocrystallization to determine the binding mechanism of cobimetinib with TEAD.
  • Tested cobimetinib in mouse models of lung and hepatocellular carcinoma.
  • Assessed cobimetinib's ability to overcome resistance to other cancer drugs.

Main Results:

  • Identified cobimetinib as a potent inhibitor of the YAP-TEAD complex.
  • Cobimetinib binds to the TEAD lipid pocket, disrupting TEAD palmitoylation.
  • Cobimetinib demonstrated efficacy in suppressing tumor growth and tumorigenesis in vivo.
  • Showed that cobimetinib can overcome resistance to MEK inhibitors, sorafenib, and lenvatinib.

Conclusions:

  • Cobimetinib is a promising therapeutic agent targeting the YAP-TEAD complex in cancers.
  • The developed HTS assay provides a strategy for discovering novel YAP-TEAD inhibitors.
  • Cobimetinib enhances the efficacy of existing cancer therapies, offering new treatment avenues.

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