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MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

ABSTRACT: Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have 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 to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor 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, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor 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 MPNST from the Phase 1/2 study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers, however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ~10% of cancer patients with this biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240145 | GEO | 2023/08/09

REPOSITORIES: GEO

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Project description:PRMT5 is the major enzyme that catalyzes the symmetric dimethylation of arginine (sDMA) in mammalian cells. Its activity is crucial for many biological processes including transcriptional regulation, mRNA processing, as well as DNA damage and repair. However, the protein substrates identified for PRMT5 have yet been limited in numbers, hindering the understanding of PRMT5 functions in normal as well as diseased cells. Herein we developed an optimized strategy for proteomic profiling of cellular sDMA and apply it to the discovery of novel PRMT5 substrates. Our results show that a combination of proteolytic digestion by the metalloprotease ulilysin and using electron-transfer dissociation with supplemental activation as the mass spectrometry method significantly increased sDMA site identification and localization after immuno-affinity enrichment. By employing SILAC-based differential quantitative proteomic approach and a PRMT5 specific inhibitor, we identified 325 sDMA sites being regulated by PRMT5, 220 being novel sites, which greatly expanded the number of PRMT5 substrates. Biochemical studies confirmed the newly discovered PRMT5 substrate, Plasminogen activator inhibitor 1 RNA-binding protein (SERBP1) and revealed that the RGG/RG motif in the central region of SERBP1 contains both PRMT5-catalyzed sDMA and Type I PRMT-catalyzed asymmetric dimethylation of arginine (aDMA). Unexpectedly, using the optimized methylarginine profiling strategy, we also discovered arginine trimethylation, a previously unknown type of modification, on the central RGG/RG region of SERBP1. By mutational studies we demonstrated that the trimethyl modification on R172 of SERBP1 regulates its recruitment to stress granule (SG) under oxidative stress, indicating a functional role of arginine trimethylation in the cell. Overall, the optimized profiling strategy not only enabled the identification of extensive, non-overlapping sDMA sites and novel PRMT5 substrates, but also revealed a potentially important new PTM, arginine trimethylation. The work lays the foundation for further investigations on the functional interplay of different methylation modifications on arginines, especially in the heavily methylated RGG/RG motif of many RNA-binding proteins.

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MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

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