Discovery of Pan-TEAD Inhibitors That Disrupt YAP-TEAD Interaction as a Potential Therapy for Gastric Cancers and Mutant KRAS and EGFR Lung Cancers

Discovery of Pan-TEAD Inhibitors That Disrupt YAP-TEAD Interaction as a Potential Therapy for Gastric Cancers and Mutant KRAS and EGFR Lung Cancers

ACS Medicinal Chemistry Letters

doi/10.1021/acsmedchemlett.5c00590

https://doi.org/10.1021/acsmedchemlett.5c00590

Ramesh Kumar, Joanne Thian, Joel D. W. Toh, Noorul Farzana, Jialin Sun, Congbao Kang, Suet Mei Crystal Low, Sheena Wee, Zijie Lim, Jayantha Gunaratne, Hui Mun Loh, Srinivasaraghavan Kannan, Chandra S. Verma, Sayan Chakraborty, Wanjin Hong

Hippo signaling, cancer, TEAD inhibitors, EGFR, KRAS, drug resistance, Monotherapy, combination therapy

26 February 2026

Kumar, R., Thian, J., Toh, J. D. W., Farzana, N., Sun, J., Kang, C., Low, S. M. C., Wee, S., Lim, Z., Gunaratne, J., Loh, H. M., Kannan, S., Verma, C. S., Chakraborty, S., & Hong, W. (2026). Discovery of Pan-TEAD inhibitors that disrupt YAP-TEAD interaction as a potential therapy for gastric cancers and mutant KRAS and EGFR lung cancers. ACS Medicinal Chemistry Letters, 17(3), 649–661. https://doi.org/10.1021/acsmedchemlett.5c00590

Dysfunction of Hippo signaling resulting in elevated YAP/TAZ-TEAD activity is commonly associated with tumorigenesis and represents a therapeutic target for cancer. Drug resistance is a significant factor undermining the efficacy of cancer therapy. In this study, we identified a class of covalent small molecules with a vinyl sulfone warhead binding to the conserved cysteine of the TEAD and disrupting its interaction with YAP. These compounds (particularly CPD10 and CPD13) strongly inhibited proliferation and colony formation of cancer cell lines with altered Hippo signaling. Moreover, the TEAD dependency of gastric cancer cells enhanced their sensitivity to CPD10 and CPD13 treatment. Importantly, the pan-TEAD inhibitors also promoted synergistic cell death in EGFR- and KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) cells, which may eventually overcome drug resistance associated with the use of FDA-approved compounds. Therefore, we uncover a novel class of vinyl sulfone warhead-bearing pan-TEAD inhibitors with potential for treating gastric and mutant KRAS and EGFR lung cancers.

Publisher Copyright

This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Individual Research Grant (OF-IRG)
Grant Reference no. : MOH-000378-00 and MOH-001115-00

This research / project is supported by the Agency for Science, Technology and Research (A*STAR) - Career development Fund
Grant Reference no. : CDF 212D800077

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi/10.1021/acsmedchemlett.5c00590.

https://oar.a-star.edu.sg/communities-collections/articles/23458

1948-5875
1948-5875

Experimental Drug Development Centre