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

  • Nat Cancer. 2024 Apr 2. doi: 10.1038/s43018-024-00754-9.
Emilie A Chapeau  1 ,  Laurent Sansregret  2 ,  Giorgio G Galli  2 ,  Patrick Chène  2 ,  Markus Wartmann  2 ,  Thanos P Mourikis  2 ,  Patricia Jaaks  2 ,  Sabrina Baltschukat  2 ,  Ines A M Barbosa  2 ,  Daniel Bauer  2 ,  Saskia M Brachmann  2 ,  Clara Delaunay  2 ,  Claire Estadieu  2 ,  Jason E Faris  3 ,  Pascal Furet  2 ,  Stefanie Harlfinger  2  4 ,  Andreas Hueber  2 ,  Eloísa Jiménez Núñez  2 ,  David P Kodack  3 ,  Emeline Mandon  2 ,  Typhaine Martin  2 ,  Yannick Mesrouze  2 ,  Vincent Romanet  2 ,  Clemens Scheufler  2 ,  Holger Sellner  2 ,  Christelle Stamm  2 ,  Dario Sterker  2 ,  Luca Tordella  2 ,  Francesco Hofmann  2  5 ,  Nicolas Soldermann  2 ,  Tobias Schmelzle  6
Affiliations
  • 1. Novartis BioMedical Research, Basel, Switzerland. [email protected].
  • 2. Novartis BioMedical Research, Basel, Switzerland.
  • 3. Novartis BioMedical Research, Cambridge, MA, USA.
  • 4. AstraZeneca, Oncology R&D, Cambridge, UK.
  • 5. Pierre Fabre Group, R&D Medical Care, Toulouse, France.
  • 6. Novartis BioMedical Research, Basel, Switzerland. [email protected].
PMID: 38565920 DOI: 10.1038/s43018-024-00754-9
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.

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