Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers

Our plain-English summary of Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers, by E.A. Chapeau, L. Sansregret, G.G. Galli, et al (Nature Cancer, 2024).

The study

• Authors: E.A. Chapeau, L. Sansregret, G.G. Galli, P. Chène, M. Wartmann, T.P. Mourikis, P. Jaaks, S. Baltschukat, I.A.M. Barbosa, D. Bauer, S.M. Brachmann, C. Delaunay, C. Estadieu, J.E. Faris, P. Furet, S. Harlfinger, A. Hueber, E. Jiménez Núñez, D.P. Kodack, E. Mandon, T. Martin, Y. Mesrouze, V. Romanet, C. Scheufler, H. Sellner, C. Stamm, D. Sterker, L. Tordella, F. Hofmann, N. Soldermann, T. Schmelzle
• Journal: Nature Cancer
• Published: 2024;5(7):1102-1120
• Cited by: 145 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

© 2024. The Author(s).

In plain English

This article reported laboratory and animal experiments with IAG933, an experimental drug designed to block YAP from binding TEAD. The study did not examine asbestos exposure. Mesothelioma appeared only as human cancer cell lines and tumors grown in mice and rats. In mesothelioma cell lines, IAG933 reduced TEAD target gene activity (IC50 between 11 and 26 nM) and growth (GI50 between 13 and 91 nM). In rats with MSTO-211H mesothelioma tumors, tumors stopped growing at 10 mg per kg, and complete regression occurred at 30 mg per kg in four of five animals, without weight loss. A related compound, YTP-75, produced significant tumor responses in seven of nine patient-derived mesothelioma models in mice. In other cancer models, combinations with other targeted drugs gave stronger responses. For example, in pancreatic tumor models tested with one mouse per model and treatment, 8 of 12 (66%) showed regression or near stasis with a triple combination. The authors concluded the data support IAG933 as a combination partner with MAPK pathway-based drugs. They noted sample sizes were not statistically predetermined and most experiments were not blinded.

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: cell-line experiments and animal (mouse and rat xenograft) experiments
• Who was studied: Human cancer cell lines (including mesothelioma lines such as MSTO-211H and NCI-H226; 103 lines in one profiling panel) and human tumors grown in female nude mice, SCID mice and female nude rats; no human patients or asbestos-exposed people were studied
• Exposure: The exposure studied was the experimental drug IAG933 and related compounds (YTP-75, YTP-13 and others), alone and combined with other cancer drugs (osimertinib, capmatinib, lapatinib, trastuzumab, JDQ443, MRTX1133, dabrafenib, trametinib, LTT462, naporafenib); asbestos was not studied
• Main results:
  • In MSTO-211H and NCI-H226 mesothelioma cells treated for 24 h, IAG933 inhibited expression of TEAD target genes CCN1, ANKRD1 and CCN2 with IC50 values between 11 and 26 nM
  • In mesothelioma cell lines, IAG933 showed growth inhibition (GI50) values between 13 and 91 nM
  • In mice with MSTO-211H tumors in the pleura, IAG933 prevented morbidity from tumor burden, with responses sustained over 4 weeks
  • In a rat MSTO-211H xenograft model after 2 weeks of daily dosing, tumor stasis occurred at 10 mg per kg, and complete regression occurred at 30 mg per kg in four of five animals; no body weight loss was observed
  • In nine patient-derived mesothelioma xenograft models in mice treated with YTP-75, significant tumor responses occurred in seven of nine: deep regressions in three NF2-altered models and durable stasis in four models without reported Hippo alterations
  • In the EBC-1 MET-amplified lung cancer model in mice, IAG933 plus capmatinib caused profound tumor shrinkage, while IAG933 alone showed no activity
  • In a mouse study of 12 pancreatic cancer patient-derived xenograft models with different KRAS mutations, 8 models (66%) showed tumor regression or near stasis with a triple combination including YTP-75
  • The pancreatic patient-derived xenograft experiment used one mouse per model per treatment
  • In a patient-derived non-small cell lung cancer model in mice, JDQ443 plus IAG933 produced no tumor regrowth for 30 days after treatment ended
• The authors' conclusion: The authors concluded that their preclinical data support using IAG933 as a combination partner with MAPK pathway-based drugs
• Limitations the authors state:
  • Sample sizes were not determined by a statistical method
  • Blinding was applied only during genomics data processing, not in other experiments
  • Sex of the tumor models was not considered
  • Further experiments are needed to clarify how the drug combinations work

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Mesothelioma, Colorectal Cancer.

Related studies

• Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma — R. Cunningham, S. Jia, et al. (2025)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity — L. Cao, J. Yang, et al. (2025)
• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)

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