Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma

Abstract

Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo. These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.

Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations

“…Quinacrine decreases YAP expression in NF2 mutant cells (Figure 4A), although the specific mechanism of action remains to be determined. Tang et al recently identified preclinical TEAD inhibitors for NF2-deficient mesothelioma, although toxicity studies have not been reported for these compounds (Tang et al, 2021). The preclinical success of TEAD inhibitors compliments our findings and highlights the potential benefits for repurposed drugs.…”

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

“…Therefore, it is a promising target for suppressing tumor progression and drug resistance [ 20 ]. Several YAP inhibitors have been discovered, including dasatinib, statin, pazopanib, verteporfin, and dobutamine [ 98 , 99 ]. Most drugs attenuate YAP-dependent transcription by inhibiting its nuclear translocation.…”

“…Although verteporfin is clinically used as a photosensitizer for photodynamic therapy, its off-target side effects and optimal dosage for anti-tumor effects should be considered. Recently developed drugs, including CA3, can potently and selectively interfere with the bond between YAP1 and TEAD [ 98 , 99 ]. These drugs may be valuable for targeting YAP in lung cancer.…”

Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine

“…This effect was initially demonstrated by two small-molecule inhibitors of TEAD palmitoylation, as well as by genetic studies. These observations were found both in vitro as well as in vivo [31][32][33]. Specifically, the inhibition of YAP1 activation and the subsequent reduction of already established tumors in vivo clearly demonstrate that YAP1 is a driver of tumor maintenance in malignant mesothelioma with the Hippo pathway or NF2 deletions.…”

“…Specifically, the inhibition of YAP1 activation and the subsequent reduction of already established tumors in vivo clearly demonstrate that YAP1 is a driver of tumor maintenance in malignant mesothelioma with the Hippo pathway or NF2 deletions. Furthermore, NF2 deletions are also found in other tumor types such as renal cell carcinoma, cervical squamous cell carcinoma, schwannomas and meningiomas, which may hence respond equally well to the inhibition of YAP1 activation [33,34].…”