دورية أكاديمية
Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.
| العنوان: | Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor. |
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| المؤلفون: | Moure CJ; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Vara B; Department of Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey., Cheng MM; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Sondey C; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Muise E; Department of Data and Genome Sciences, Merck & Co., Inc., Rahway, New Jersey., Park E; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Vela Ramirez JE; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., Rahway, New Jersey., Su D; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., D'Souza S; Department of Discovery Oncology, Merck & Co., Inc., Rahway, New Jersey., Yan Q; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Yeung CS; Department of Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey., Zhang M; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Mansueto MS; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Linn D; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Buchanan M; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Foti R; Department of PPDM, Merck & Co., Inc., Rahway, New Jersey., DiMauro E; Department of Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey., Long B; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey., Simov V; Department of Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey., Barry ER; Department of Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2024 Aug 01; Vol. 23 (8), pp. 1095-1108. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Hepatocyte Growth Factor*/metabolism , Transcription Factors*/metabolism , Transcription Factors*/antagonists & inhibitors , Proto-Oncogene Proteins c-met*/antagonists & inhibitors , Proto-Oncogene Proteins c-met*/metabolism , Signal Transduction*/drug effects , Adaptor Proteins, Signal Transducing*/metabolism , Adaptor Proteins, Signal Transducing*/antagonists & inhibitors , YAP-Signaling Proteins* , Drug Resistance, Neoplasm*/drug effects, Humans ; Animals ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Small Molecule Libraries/pharmacology ; TEA Domain Transcription Factors ; Cell Proliferation/drug effects |
| مستخلص: | Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. In addition, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A, demonstrating potent and specific inhibition of YAP1/TAZ-TEAD-mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance. (©2024 American Association for Cancer Research.) |
| المشرفين على المادة: | 67256-21-7 (Hepatocyte Growth Factor) 0 (Transcription Factors) EC 2.7.10.1 (Proto-Oncogene Proteins c-met) 0 (Adaptor Proteins, Signal Transducing) 0 (YAP-Signaling Proteins) 0 (YAP1 protein, human) 0 (Small Molecule Libraries) EC 2.7.10.1 (MET protein, human) 0 (TEA Domain Transcription Factors) |
| تواريخ الأحداث: | Date Created: 20240501 Date Completed: 20240801 Latest Revision: 20240801 |
| رمز التحديث: | 20240801 |
| DOI: | 10.1158/1535-7163.MCT-23-0538 |
| PMID: | 38691847 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-23-0538 |