Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model
TEAD transcription factors enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the TEAD lipid pocket is an established path to inhibit the oncogenic activities of cofactors YAP and TAZ. Here we present two pan-TEAD inhibitors, GNE-8025 and its in vivo brain-penetrant derivative GNE-2181, that covalently bind the lipid pocket at a conserved cysteine. Both small molecules show growth inhibition of YAP-driven tumor cells in vitro and in vivo. Moreover, we show that GNE-8025 increases the activity of a broad range of MAPK pathway inhibitors in vitro as well as the KRASG12C inhibitor Divarasib both in vitro and in vivo. In addition, GNE-2181 inhibits growth of an intracranial tumor model in vivo. Altogether we present a next-generation class of TEAD inhibitors representing a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies. Hyperactive YAP/TAZ-TEAD signaling is a common mechanism of resistance to targeted therapies. Here, the authors discover that covalent pan-TEAD inhibitors, including a brain-penetrant inhibitor, decrease YAP activity and suppress both peripheral and intracranial tumor growth.
Authors
- Consuelo Torrini (ORCID: https://orcid.org/0000-0003-2743-0839)
- Vishal Verma (ORCID: https://orcid.org/0000-0001-7600-4372)
- Danilo Maddalo (ORCID: https://orcid.org/0000-0002-3228-1703)
- Luca Gerosa (ORCID: https://orcid.org/0000-0001-6805-9410)
- Scott A. Foster (ORCID: https://orcid.org/0000-0002-2773-7999)
- Priscilla K. Brastianos (ORCID: https://orcid.org/0000-0003-4470-8425)
- Naema Nayyar (ORCID: https://orcid.org/0000-0003-3436-8404)
- Julien Tremblay (ORCID: https://orcid.org/0000-0002-6085-3481)
- Ramsay E. Beveridge
- Nicole M. Sodir (ORCID: https://orcid.org/0000-0002-9919-2190)
- Anwesha Dey (ORCID: https://orcid.org/0000-0001-5688-5942)
- Peter Hsu (ORCID: https://orcid.org/0000-0002-9381-6564)
- Alissa D. Guarnaccia (ORCID: https://orcid.org/0000-0003-4195-2158)
- Joshua D. Webster (ORCID: https://orcid.org/0000-0002-0014-1685)
- Gözde Ulas
- Thijs J. Hagenbeek (ORCID: https://orcid.org/0000-0002-0921-2910)
- James R. Hawley (ORCID: https://orcid.org/0000-0003-4744-5552)
- Maria Lorenzo
- Jim Nonomiya
- Rina Fong (ORCID: https://orcid.org/0000-0001-9707-6869)
- Paul Beroza (ORCID: https://orcid.org/0000-0002-9407-1648)
- Miaoran Ning (ORCID: https://orcid.org/0000-0002-2949-4759)
- Gladys de Leon Boenig (ORCID: https://orcid.org/0000-0002-8314-1188)
- Sayantanee Paul (ORCID: https://orcid.org/0000-0003-4616-1216)
- Xiaosai Yao (ORCID: https://orcid.org/0000-0001-9729-0726)
- Paola Di Lello (ORCID: https://orcid.org/0000-0002-9683-926X)
- Shu Chen (ORCID: https://orcid.org/0009-0006-2406-0309)
- Yichen Chen (ORCID: https://orcid.org/0000-0003-4385-4180)
- Lisha Wang (ORCID: https://orcid.org/0000-0002-6482-1073)
- Wendy Lee (ORCID: https://orcid.org/0000-0002-9959-8529)
- Jeffrey Lau
- Julie Weng
- Jeff Hung
- Elizabeth Levy
- Jeff Eastham
- Debra Dunlap (ORCID: https://orcid.org/0000-0001-7042-2987)
- Marc Hafner (150206)
- Jennie R. Lill
- Jessica Preston
- Jennifer A. Lacap
- Pablo Saenz-Lopez Larrocha
- Scott Martin
- Victoria Pham
- Marta H. Kubala
- Frances Shanahan
- Zora D. Modrusan
- Jason Zbieg
- Mirunalini Ravichandran
- Bryan Chan
- Russell Smith
- Eva Lin
- Le An
- Thomas Hunsaker
- Christy Ong
Institutions
- Harvard University (US)
- Massachusetts General Hospital (US)
- Gene Therapy Laboratory (FR)
- Paraza Pharma (Canada) (CA)
- Genomic Health (United States) (US)
- Sunesis (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-27
- DOI
- https://doi.org/10.1038/s41467-026-74722-5
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 0.00