MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP-deleted cancer Journal Article
| Authors: | Engstrom, L. D.; Aranda, R.; Waters, L.; Moya, K.; Bowcut, V.; Vegar, L.; Trinh, D.; Hebbert, A.; Smith, C. R.; Kulyk, S.; Lawson, J. D.; He, L.; Hover, L. D.; Fernandez-Banet, J.; Hallin, J.; Vanderpool, D.; Briere, D. M.; Blaj, A.; Marx, M. A.; Rodon, J.; Offin, M.; Arbour, K. C.; Johnson, M. L.; Kwiatkowski, D. J.; Jänne, P. A.; Haddox, C. L.; Papadopoulos, K. P.; Henry, J. T.; Leventakos, K.; Christensen, J. G.; Shazer, R.; Olson, P. |
| Article Title: | MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP-deleted cancer |
| Abstract: | Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmaco-logic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. © 2023 The Authors. |
| Keywords: | protein expression; unclassified drug; human cell; clinical trial; nonhuman; flow cytometry; mouse; phenotype; cell viability; melanoma; apoptosis; phase 2 clinical trial; carcinoma, non-small-cell lung; lung neoplasms; animal experiment; animal model; tumor biopsy; in vivo study; cell differentiation; antineoplastic activity; cancer cell culture; in vitro study; tumor regression; tumor xenograft; enzyme inhibitor; cell line, tumor; lung tumor; xenograft; enzyme inhibitors; sequence alignment; bioassay; tumor cell line; erythroid cell; hematopoietic cell; immunoblotting; mesothelioma; fibroblast; bone marrow cell; phase 1 clinical trial; x ray crystallography; surface plasmon resonance; malignant peripheral nerve sheath tumor; myeloid differentiation factor 88; synthesis; lethality; lipocortin 5; rna extraction; rna sequence; non small cell lung cancer; protein arginine methyltransferase; protein arginine methyltransferase 5; chemical agent; radioimmunoprecipitation; gallbladder adenocarcinoma; protein-arginine n-methyltransferases; humans; human; article; cell viability assay; ic50; gene set enrichment analysis; cell cycle assay; malignant neoplasm; hct 116 cell line; lethal mutation; synthetic lethal mutations; prmt5 protein, human; 6 n,n' dimethylarginine; mrtx1719; apoptosis assay |
| Journal Title: | Cancer Discovery |
| Volume: | 13 |
| Issue: | 11 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-11-01 |
| Start Page: | 2412 |
| End Page: | 2431 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-23-0669 |
| PUBMED: | 37552839 |
| PROVIDER: | scopus |
| PMCID: | PMC10618744 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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