8Q68

Crystal structure of TEAD1-YBD in complex with irreversible compound SWTX-143

Summary for 8Q68

• Entry DOI: 10.2210/pdb8q68/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, ~{N}-[(3~{S})-5-azanyl-1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2~{H}-quinolin-3-yl]propanamide (3 entities in total)
• Functional Keywords: irreversible covalent inhibitor, mesothelioma tumor regression, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 55945.49

Authors

Ciesielski, F.,Spieser, S.A.H.,Marchand, A.,Gwaltney, S.L. (deposition date: 2023-08-11, release date: 2023-10-04, Last modification date: 2024-11-20)

Primary citation

Hillen, H.,Candi, A.,Vanderhoydonck, B.,Kowalczyk, W.,Sansores-Garcia, L.,Kesikiadou, E.C.,Van Huffel, L.,Spiessens, L.,Nijs, M.,Soons, E.,Haeck, W.,Klaassen, H.,Smets, W.,Spieser, S.A.,Marchand, A.,Chaltin, P.,Ciesielski, F.,Debaene, F.,Chen, L.,Kamal, A.,Gwaltney, S.L.,Versele, M.,Halder, G.A.
A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models.
Mol.Cancer Ther., 23:3-13, 2024

PubMed Abstract: The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.

PubMed: 37748190
DOI: 10.1158/1535-7163.MCT-22-0681

Experimental method

X-RAY DIFFRACTION (1.58 Å)