Abstract Methylthioadenosine phosphorylase (MTAP) homozygous deletion occurs in 10-15% of all human cancers. Loss of MTAP result in methylthioadenosine (MTA) accumulation. PRMT5, which is a type II arginine methyltransferase that regulates multiple essential cellular functions via symmetric dimethylation of arginine (SDMA) in target proteins, was identified as a synthetic lethal target for MTAP del cancers. MTA-cooperative PRMT5 inhibitors may exhibit better safety profiling compared to first generation PRMT5i (which observe limiting heme-related toxicities in clinical), which preferentially inhibiting PRMT5 in MTAP del cancer cells to normal cells. HSK41959-2 is a MTA-cooperative PRMT5 inhibitor, which could selectively inhibits PRMT5 in the present of MTA with IC50 was 0. 80 nM. In HCT116 MTAP Deleted cell line, HSK41959-2 significantly inhibits the cell proliferation with GI50 of 19. 89 nM, which was around 45-fold selectivity in HCT116 cell line. In SDMA assay, HSK41959-2 also showed high potency in HCT116 MTAP-del cell line with IC50 was 3. 39 nM, and much weaker in HCT116 MTAP-WT cell line with IC50 was 499 nM, around 147-fold selectivity. In vitro CD34+ Hematopoietic stem cell cell proliferation assay was used for evaluate the heme-related toxicities. HSK41959-2 weakly inhibited the cell proliferation with IC50 of 544 nM while the first generation PRMT5i with IC50 was 35. 39 nM. This results indicated HSK41959-2 may has lower heme-related toxicities compared with the first generation PRMT5i. In the HCT116 MTAP-del xenograft model, daily orally administrated with 25 mpk and 100 mpk HSK41959-2 showed significant tumor growth inhibition, with TGI were 62% and 88%, and PRMT5-dependent SDMA protein inhibition were 89% and 95%, respectively. Meanwhile in the HCT116 MTAP-WT xenograft model, HSK41959-2 did not show tumor growth inhibition at 100 mpk. In conclusion, HSK41959-2 is a promising oral MTA-cooperative PRMT5 inhibitor, it was nominated as a development candidate. Citation Format: Pangke Yan, Ju Wang, Meilin Qian, Xiaojuan Yu, Yao Li, Haoliang Zhang, Lihua Tao, Rui Kou, Teng Hu, Pingming Tang, Hongjiao Dong, Aipin Wu, Maotao He. HSK41959-2: An oral MTA-cooperative PRMT5 inhibitor for MTAP deleted cancer 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 4595.
Yan et al. (2024) studied this question.