Chapeau, Emilie, Schmelzle, Tobias and Soldermann, Nicolas (2024) Direct and selective pharmacological disruption of the YAP-TEAD interface inhibits cancers with genetic alterations in the Hippo and RAS-MAPK pathways. Nature Cancer.

Abstract

YAP-TEAD protein-protein interaction is a crucial event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Here we present IAG933, the first molecule able to potently disrupt YAP/TAZ and TEADs protein-protein interaction with suitable properties to enter clinical trials. Biochemical and cellular assays demonstrate specific abrogation of the interaction between YAP/TAZ coactivators and all four TEAD isoforms. Direct pharmacological disruption leads to YAP eviction from chromatin, and consequent engagement of TEADs co-repressor VGLL4. with concomitant decrease in Hippo-related transcriptional activity thereby inducing cancer cell killing. Compound selectivity was shown in rescue experiments, consistent with the correlation observed between pharmacological and genetic sensitivity profiles. In preclinical experiments, deep tumor regression is observed in mesothelioma xenograft models, at doses tolerated in both mice and rats. IAG933 anti-tumor efficacy is also observed in other Hippo-mutated cancer models as well as in combination with RTK, RAS, RAF and MAPK inhibitors, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a robust rationale of using IAG933 as monotherapy or combination therapy, with the potential to treat various patient populations with high unmet medical need.

Item Type:	Article
Keywords:	YAP, TEAD, PPI inhibitor, mesothelioma, combination therapies, Hippo pathway
Date Deposited:	16 May 2024 00:45
Last Modified:	16 May 2024 00:46
URI:	https://oak.novartis.com/id/eprint/50282