Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature cancer			2024 Apr 02		Nat Cancer

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 + 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
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