Issue 11, 2023

A covalent inhibitor of the YAP–TEAD transcriptional complex identified by high-throughput screening

Abstract

Yes-associated protein (YAP), the master transcriptional effector downstream of the Hippo pathway, regulates essential cell growth and regenerative processes in animals. However, the activation of YAP observed in cancers drives cellular proliferation, metastasis, chemoresistance, and immune suppression, making it of key interest in developing precision therapeutics for oncology. As such, pharmacological inhibition of YAP by targeting its essential co-regulators, TEA domain transcription factors (TEADs) would likely promote tumor clearance in sensitive tumor types. From a fluorescence polarization-based high throughput screen of over 800 000 diverse small molecules, here we report the identification of a pyrazolopyrimidine-based scaffold that inhibits association of YAP and TEADs. Medicinal chemistry-based optimization identified mCMY020, a potent, covalent inhibitor of TEAD transcriptional activity that occupies a conserved, central palmitoylation site on TEADs.

Graphical abstract: A covalent inhibitor of the YAP–TEAD transcriptional complex identified by high-throughput screening

Supplementary files

Article information

Article type
Paper
Submitted
29 3 2023
Accepted
19 8 2023
First published
29 8 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 894-905

A covalent inhibitor of the YAP–TEAD transcriptional complex identified by high-throughput screening

K. Nutsch, L. Song, E. Chen, M. Hull, A. K. Chatterjee, J. J. Chen and M. J. Bollong, RSC Chem. Biol., 2023, 4, 894 DOI: 10.1039/D3CB00044C

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements