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Development of YAP-TEAD inhibitors derived from flufenamic acid

Project description

The YAP-TEAD transcriptional complex, the downstream effector of the Hippo signaling pathway, activates the expression of anti-apoptotic genes as well as proliferation ones. In malignant pleural mesothelioma (MPM), a rare and orphan cancer representing less than 1% of known cancers, multiple genetic mutations in the Hippo pathway have been identified. Thus, YAP is overexpressed, in a direct or indirect manner, in more than 70% of MPM cases. Because of its aggressiveness, with a median patient survival of one year after diagnostic, it is now critical to develop effective treatments. As YAP oncogenic function is only activated upon its binding to TEAD, inhibiting YAP-TEAD complex formation should lead to new therapies against MPM. In collaboration with the SGC at Toronto, flufenamic acid derivatives have been designed to bind in a hydrophobic pocket of TEAD, preventing its palmitoylation and therefore YAP-binding. These compounds are synthesized through a Buchwald N-arylation between anilines and corresponding methyl-2-bromobenzoates.

Research team

Name: Léa Mélin, M.Sc
Supervisor: Alexandre Gagnon (UQAM)
Laureate: Doctoral scholarship 2019 and 2020

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