Author: Endlicher, Rene ; Schmidt, Monika ; Zemanova, Lucie ; Vernerova, Tereza ; Haleckova, Annamaria ; Salamonova, Katerina ; Bubelova, Petra ; Musilek, Kamil ; Benek, Ondrej ; Febda Kurnia, Haka Fajriana ; Joklova, Andrea ; Hurdalek, Jan ; Syrova, Veronika

Cyclophilin D (CypD) is a mitochondrial enzyme widely accepted as a regulator of the mitochondrial permeability transition pore (mPTP). Excessive opening of mPTP is associated with mitochondrial dysfunction and the development of various diseases; thus, suppression of mPTP opening through CypD inhibition presents a promising therapeutic approach. However, only a limited number of selective CypD inhibitors are currently available. In this study, 10 derivatives of 2-(benzyloxy)arylurea similar or identical to previously published CypD/mPTP inhibitors were synthesized. Unlike the original reports that assessed the opening of mPTP at the cellular level, the compounds were tested directly on the purified CypD enzyme to validate their putative mechanism of action. Additionally, the effect of the selected compounds was tested on isolated mitochondria. The obtained results show that the compounds are only weak inhibitors of CypD and mPTP opening, which is in contrast to previous conclusions drawn from the unspecific cellular JC-1 assay.

EMBO Reports

Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription

Article

Author: Harvey, Kieran F ; Dawson, Mark A ; Rosenbluh, Joseph ; Parker, Benjamin L ; Thio, Niko ; Tang, Tracy T ; Vissers, Joseph Ha ; Manning, Murray ; Chan, Yih-Chih ; Mohan, Varshini ; Kulkarni, Aishwarya ; Post, Leonard

AbstractThe Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

100 Deals associated with TEAD inhibitors (Beactica)

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	SE	Beactica Therapeutics AB	16 May 2023

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