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Development of inhibitors of transcription factors

The Hippo pathway controls cell proliferation and apoptosis in multicellular organisms to assure normal tissue development and organ growth. The Hippo pathway is composed of a cascade of kinases that comprises four kinases, MST1/2, SAV, MOB1 and LATS1/2 that control the localization of YAP and TAZ. The downstream effector of the Hippo pathway is the transcription factor YAP–TEAD which is responsible for the transcription of target genes such as CTGF, Cyr61 and Axl.

In the active Hippo pathway (ON), the phosphorylation of YAP (Yes associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) leads to their retention and degradation in the cytoplasm. In the inactive pathway (OFF), YAP and TAZ are phosphorylated and then migrate in the nucleus to form a transcriptionally active complex with TEAD. Dysregulation of the Hippo pathway and overexpression of YAP, TAZ or TEAD have been observed in various types of cancers, leading to overexpression of genes that confer unique properties to cancer cells such as excessive proliferation, invasiveness and evasion from immune system. The Hippo pathway thus represents a target of choice in the development of drugs for the treatment of cancer.

YAP TEAD interfaces.tiff

The Hippo pathway can be modulated by stimulating upstream kinases that will thus favor the phosphorylation and retention of YAP in the cytoplasm. However, this approach is challenging since these compounds must act as activators, a mode of action which is difficult to optimize. The Hippo pathway can also be modulated by preventing the formation of the YAP–TEAD complex. The inspection of the YAP–TEAD structure shows that YAP wraps itself around TEAD, creating three interfaces called 1 (red), 2 (orange) and 3 (blue). Peptides that disrupt these interactions have been reported, but these compounds show limitations such as poor pharmacokinetic profiles.

Because it is highly disordered and because it lacks well defined pockets, YAP is a poor target for drug discovery. On the contrary, TEAD is much more organized and can be targeted by small organic molecules. Studies have shown the presence of a palmitic acid molecule which is connected to a cysteine located at the entry of the pocket. TEAD's palmitoylation appears to play an important role in the obtention of a transcriptionally active YAP–TEAD complex. Due to its hydrophobic character, the palmitic acid pocket is particularly suitable to accommodate small molecules. Various compounds have been reported in the literature to bind in this pocket.


Our group is actively working on the development of inhibitors of the YAP–TEAD transcription factor that target the palmitic pocket and that inhibit the expression of associated genes. Compounds are synthesized in our laboratory and are then tested with partners in biophysical assays to evaluate their affinity to TEAD. Their capacity to prevent the auto-palmitoylation of TEAD is then investigated using mass spectrometry while their impact on gene expression is studied using luciferase assays and qPCR. Our research on YAP–TEAD is performed in collaboration with experts in the fields of biophysics, structural biology, biochemistry and cell biology. Docking studies are conducted in our group to propose a binding mode for our compounds and guide our SAR activities.

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