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Ref Type Journal Article
PMID (38565920)
Authors Chapeau EA, Sansregret L, Galli GG, Chène P, Wartmann M, Mourikis TP, Jaaks P, Baltschukat S, Barbosa IAM, Bauer D, Brachmann SM, Delaunay C, Estadieu C, Faris JE, Furet P, Harlfinger S, Hueber A, Jiménez Núñez E, Kodack DP, Mandon E, Martin T, Mesrouze Y, Romanet V, Scheufler C, Sellner H, Stamm C, Sterker D, Tordella L, Hofmann F, Soldermann N, Schmelzle T
Title Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IAG933 IAG933 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
IAG933 IAG 933|IAG-933 IAG933 disrupts the interaction between yes-associated protein 1 (YAP) and the transcription factor TEAD, potentially leading to decreased YAP/TEAD-dependent gene expression and tumor growth inhibition (PMID: 38565920).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Dabrafenib + IAG933 Preclinical - Cell culture Actionable In a preclinical study, the combination of IAG933 and Tafinlar (dabrafenib) inhibited proliferation of colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 38565920). 38565920
BRAF V600E colorectal cancer sensitive Dabrafenib + IAG933 + LTT462 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of IAG933, Tafinlar (dabrafenib), and LTT462 inhibited proliferation of colorectal cancer cell lines harboring BRAF V600E in culture and resulted in greater tumor growth inhibition compared to either agent alone in a cell line xenograft model (PMID: 38565920). 38565920
BRAF V600E colorectal cancer sensitive Dabrafenib + IAG933 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of IAG933, Tafinlar (dabrafenib), and Mekinist (trametinib) inhibited proliferation of colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 38565920). 38565920