Abstract 7603: Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai

Abstract MTAP (methylthioadenosine phosphorylase) is located adjacent to the tumor-suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A) and sometimes co-deleted in 10-15% of all cancers, especially in glioblastoma, mesothelioma, and pancreatic cancers. Recent studies shown that MTAP deletions in cancer create vulnerability to synthetic lethal with the MAT2A/PRMT5/RIOK1 axis. Herein, we report the discovery of a PRMT5 inhibitor GH56, and an MAT2A inhibitor GH31, both showed promising single agent efficacy and synergy in MTAP loss tumor models. GH56 is an MTA-Cooperative PRMT5 inhibitor. In vitro, GH56 showed potent SDMA inhibition in MTAP-deleted cancer cells with an IC50 from 0. 8‒3 nM. It also showed excellent selectivity with more than 100-folds in MTAP-WT cells. In a cell panel with more than 100 cell-lines, GH56 selectively inhibited the growth of cells with MTAP-deletion while separated the cells with MTAP-WT. In the safety panel and kinase panel, GH56 all showed good selectivity. In addition, GH56 had an IC50 10 μM for hERG. In vivo, GH56 showed dose-dependent efficacy in a series MTAP-deleted models and were well tolerated. In U87MG glioblastoma CDX model, NCI-H838 NSCLC CDX model, BXPC-3/HupT4 PDAC CDX models and RT112-84 BLCA model, TGI for GH56 at high dose were all 100%. On the other hand, GH31 is a potent and selective MAT2A inhibitor. GH31 also showed excellent selectivity with MTAP-deleted and MTAP-WT cell lines. The combination of GH56 and GH31 showed synergy both in vitro and in vivo. The low dose GH31 combination with low-dose GH56 achieved the similar efficacy as high dose GH56 and a more rapid tumor regression. In view of the delayed onset of the tumor response and high dose needed by PRMT5 inhibitor (reported by clinic stage compounds), the combination of PRMT5i and MAT2Ai will be advantageous. Furthermore, both GH56 and GH31 are brain penetrant, especially for GH31, with a Kpuu 0. 6 and B/P 2. The combination of GH56 and GH31 in a brain metastasis model and a glioblastoma in situ model all showed strong synergy, demonstrated the potential for the treatment of glioblastoma and other cancer with brain metastasis. In summary, we discovered potent, selective and brain penetrant PRMT5 inhibitor GH56 and MAT2A inhibitor GH31. Both compounds are currently under evaluation in IND-enabling studies and will provide more options for MTAP-deleted cancers. Citation Format: Guiping Zhang, Jiapeng Li, Jie Jack Li. Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7603.