Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity

Our plain-English summary of Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity, by L. Cao, J. Yang, Y. Liu, et al (Advanced Science, 2025).

The study

• Authors: L. Cao, J. Yang, Y. Liu, X. Chen, Y. Shi, Y. Zhao, Y. Zhang, J. Chen, B. Li, W. Wen, L. Chen, B. Peng, L. Huang, Y. Sun, L. Zhou, M.G. Rees, M.M. Ronan, J.A. Roth, Z. Guo, J. Xing, G. Zhu, Y. Wang, B. Jiang, J. Lu, K. Zhao, W. Lu
• Journal: Advanced Science
• Published: 2025;12(48):e03277
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The TEA/ATSS (TEAD) family of transcription factors are key effectors of the Hippo pathway, exerting their function through interactions with the coactivators YAP and TAZ. Over the past five years, the development of YAP-TEAD disruptors has emerged as a central focus of both academic and industrial efforts aimed at targeting the Hippo pathway for cancer therapy. In this study, the discovery and comprehensive characterization of KG-FP-003, a potent, selective, and durable TEAD degrader is reported. KG-FP-003 exhibits superior activity compared to the lipid-binding pocket (LBP) inhibitor MYF-03-176 and the TEAD-YAP protein-protein interaction (PPI) inhibitor IAG933, efficiently degrading all TEAD isoforms at low nanomolar concentrations in a ubiquitin-proteasome system (UPS)-dependent manner. This degradation translates into more robust and sustained therapeutic responses both in vitro and in vivo. Furthermore, barcoded cell line screening revealed elevated sensitivity in several cancer types, including endometrial carcinoma, glioblastoma, ovarian epithelial tumors, and osteosarcoma. These findings position KG-FP-003 as a compelling lead candidate for TEAD isoform-selective therapies and underscore its potential utility beyond Hippo-dysregulated mesothelioma.

© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

In plain English

This laboratory drug-discovery study reported KG-FP-003, a CRBN-based PROTAC designed to degrade TEAD transcription factors, tested in human cancer cell lines and mouse xenografts. In HiBiT-tagged HEK293T cells the compound degraded all four isoforms at nanomolar concentrations (TEAD1 DC50 6 ± 4 nM, TEAD2 68 ± 15 nM, TEAD3 12 ± 5 nM, TEAD4 7 ± 5 nM). In TEAD1-mNeonGreen NCI-H1299 cells, TEAD1 depletion was near-complete within 2 h and sustained up to 12 days; degradation was minimal in CRBN-null HEK293T cells and was blocked by proteasome and neddylation inhibitors. In the mesothelioma lines NCI-H226 and MSTO-211H, antiproliferative IC50 values were 27 ± 7 nM and 47 ± 5 nM. In MSTO-211H xenografts treated for 21 days, tumour growth inhibition reached 118% at 10 mg/kg and 129% at 30 mg/kg given intraperitoneally, versus 66% for KY-001 given orally at 10 mg/kg. PRISM screening of 867 cancer cell lines identified glioblastoma (A172), endometrial (KLE), osteosarcoma (HOS) and ovarian (ES2) lines sensitive to KG-FP-003 but not to the inhibitor MYF-03-176. The authors concluded KG-FP-003 is a potent, selective, durable TEAD degrader warranting further preclinical development.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: synthesis and characterisation of a PROTAC degrader in biochemical assays, cancer cell lines and mouse xenograft models
• Who was studied: Human cell lines (HEK293T, NCI-H1299, mesothelioma NCI-H226 and MSTO-211H, glioblastoma A172, ovarian ES2 and others), a PRISM panel of 867 cancer cell lines, ICR mice for pharmacokinetics, and BALB/c nude mice bearing MSTO-211H or ES2 subcutaneous xenografts
• Exposure: The CRBN-recruiting PROTAC KG-FP-003 (and analogues such as KG-FP-009), compared with the lipid-binding pocket inhibitor MYF-03-176, the TEAD-YAP PPI inhibitor IAG933, the warhead KY-001 and an LBP-based TEAD PROTAC (compound 27); doses in cells from low nanomolar, in mice 3, 10 and 30 mg/kg intraperitoneally
• Main results:
  • KG-FP-003 degraded all four TEAD isoforms in HiBiT-tagged cells at nanomolar DC50 values
  • In TEAD1-mNeonGreen NCI-H1299 cells, TEAD1 degradation was rapid and long-lasting
  • Degradation was minimal in CRBN-null HEK293T cells and was blocked by pretreatment with IAG933, lenalidomide, MLN4924 or bortezomib
  • Antiproliferative potency in the two mesothelioma cell lines
  • Activity depended on CRBN; knockout of CRBN in MSTO-211H cells reduced the degrader's effect but not that of IAG933
  • Tumour growth inhibition by KG-FP-003 in the MSTO-211H mesothelioma xenograft over 21 days (n = 6 per group)
  • Tumour growth inhibition by the comparator KY-001 in the same model
  • The two compared agents were given by different routes: KG-FP-003 intraperitoneally, KY-001 orally
  • Pharmacokinetics in ICR male mice after 5 mg/kg intraperitoneal dosing
  • PRISM screening of 867 cell lines identified lineages sensitive to the degrader but not to the LBP inhibitor
  • RNA sequencing in A172 glioblastoma cells at 30 nM showed more transcriptional change than IAG933
  • Seven-day toxicity assessment in MSTO-211H tumour-bearing mice at 10 or 30 mg/kg showed no organ lesions
• The authors' conclusion: The authors concluded that KG-FP-003 is a potent, selective and durable TEAD degrader whose degradation efficacy, durable activity and tumour suppression across models support further preclinical development
• Limitations the authors state:
  • Validated antibodies were not available for all TEAD isoforms, so engineered HiBiT-tagged cell lines had to be used
  • HiBiT-TEAD2 could not be detected by antibody under the conditions used, attributed to low TEAD2 expression
  • Cellular CRBN binding of the PROTACs was weaker than in the biochemical assay, attributed to permeability
  • Tumour response in the ES2 ovarian xenograft was less marked than in the mesothelioma model

Topics

Medical terms in this study, explained in our Lexicon: Discovery, Carcinoma, Mesothelioma.

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