2. Academic Validation
  3. Expanding the toolbox to develop IAP-based degraders of TEAD transcription factors

Expanding the toolbox to develop IAP-based degraders of TEAD transcription factors

  • Commun Chem. 2026 Jan 19;9(1):69. doi: 10.1038/s42004-025-01871-x.
Nishma Gupta # 1 2,  Nicole Trainor # 2 3,  Mona Radwan 1 2 4,  Stephanie Nguyen 2 3,  Luke Duncan 2 3,  Andrew X Tang 2 3,  Julia Beveridge 2 3 5,  Natasha Silke 1 2,  Jumana Yousef 2 6,  Ceren Bilgilier 7,  Johannes Wachter 7,  Peter Greb 7,  Zuzana Jandova 7,  Ján Eliaš 7,  Sara Kopf 7,  Thomas Gerstberger 7,  Peggy Stolt-Bergner 8,  Nina Braun 7,  Harald Weinstabl 7,  Darryl B McConnell 7 9,  Federico Mauri 7,  Isabelle S Lucet 2 3,  John Silke 1 2,  Nicola E A Chessum 10,  Michael J Roy 11 12 13
Affiliations

Affiliations

  • 1 Inflammation Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.
  • 2 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 3 ACRF Chemical Biology Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.
  • 4 Centre for Genetic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, KSA, Saudi Arabia.
  • 5 BioCurate Pty Ltd, Carlton, VIC, Australia.
  • 6 Advanced Technology and Biology Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.
  • 7 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 8 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
  • 9 Curie.Bio, Boston, MA, USA.
  • 10 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. nicola.chessum@boehringer-ingelheim.com.
  • 11 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. michael.roy@adelaide.edu.au.
  • 12 ACRF Chemical Biology Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia. michael.roy@adelaide.edu.au.
  • 13 South Australian immunoGENomics Cancer Institute (SAiGENCI), Adelaide University, Adelaide, SA, Australia. michael.roy@adelaide.edu.au.
  • # Contributed equally.
PMID: 41554911 DOI: 10.1038/s42004-025-01871-x
Abstract

The TEAD transcription factors (TEAD1-4) are critical effectors of the Hippo pathway, forming active nuclear complexes with transcriptional co-activators YAP/TAZ to regulate cell growth/Apoptosis pathways and control fundamental processes such as organ size. Frequent dysregulation of the Hippo pathway in Cancer and the presence of druggable binding sites on TEADs make them attractive targets for development of small molecule inhibitors and degraders. Here, we identify and mechanistically characterize three unique series of bifunctional degraders that target TEAD1 via a lipid pocket and recruit different members of the Inhibitor of Apoptosis proteins (IAPs) family to effect degradation of TEAD1. We provide a detailed toolkit for structural, biophysical and cellular profiling, including the development of a cellular target engagement assay for the lipid pocket of TEAD1 and an IAP/TEAD1 ternary complex formation assay. Our study therefore provides essential resources for detailed characterization of IAP-recruiting degraders and important tools and learnings for bifunctional degraders targeted to the lipid pocket of TEADs.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z