An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Nat Cancer. 2023 Jun;4(6):812-828. doi: 10.1038/s43018-023-00577-0.

Thijs J Hagenbeek ^# ¹, Jason R Zbieg ^# ², Marc Hafner ^# ³, Rana Mroue ¹, Jennifer A Lacap ⁴, Nicole M Sodir ⁴, Cameron L Noland ⁵, Shervin Afghani ¹, Ayush Kishore ¹, Kamakoti P Bhat ¹, Xiaosai Yao ³, Stephen Schmidt ⁶, Saundra Clausen ⁶, Micah Steffek ⁶, Wendy Lee ², Paul Beroza ², Scott Martin ¹, Eva Lin ¹, Rina Fong ⁵, Paola Di Lello ⁵, Marta H Kubala ⁵, Michelle N-Y Yang ⁴, Jeffrey T Lau ⁴, Emily Chan ⁴, Alfonso Arrazate ⁴, Le An ⁷, Elizabeth Levy ⁷, Maria N Lorenzo ⁸, Ho-June Lee ¹, Trang H Pham ¹, Zora Modrusan ⁹, Richard Zang ¹⁰, Yi-Chen Chen ¹⁰, Michal Kabza ¹¹, Musaddeque Ahmed ¹², Jason Li ³, Matthew T Chang ³, Danilo Maddalo ⁴, Marie Evangelista ¹³, Xin Ye ¹⁴, James J Crawford ¹⁵, Anwesha Dey ¹⁶

Affiliations

1 Department of Discovery Oncology, Genentech, California, CA, USA.
2 Department of Discovery Chemistry, Genentech, California, CA, USA.
3 Department of Oncology Bioinformatics, Genentech, California, CA, USA.
4 Department of Translational Oncology, Genentech, California, CA, USA.
5 Department of Structural Biology, Genentech, California, CA, USA.
6 Department of Biochemical and Cellular Pharmacology, Genentech, California, CA, USA.
7 Department of Small Molecule Pharmaceutical Sciences, Genentech, California, CA, USA.
8 Department of Protein Chemistry, Genentech, California, CA, USA.
9 Department of Microchemistry, Proteomics and Lipidomics, Genentech, California, CA, USA.
10 Department of Drug Metabolism and Pharmacokinetics, Genentech, California, CA, USA.
11 Roche Polska, Warsaw, Poland.
12 Roche Canada, Mississauga, Ontario, Canada.
13 Department of Discovery Oncology, Genentech, California, CA, USA. evangem2@gmail.com.
14 Department of Discovery Oncology, Genentech, California, CA, USA. ye.xin@gene.com.
15 Department of Discovery Chemistry, Genentech, California, CA, USA. crawford.james@gene.com.
16 Department of Discovery Oncology, Genentech, California, CA, USA. dey.anwesha@gene.com.
# Contributed equally.

PMID: 37277530 DOI: 10.1038/s43018-023-00577-0

Abstract

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-147214

GNE-7883

98.49%, pan-TEAD Inhibitor

YAP

Cancer

Name
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