MS023 is a potent, selective, and cell-active inhibitor of type I protein arginine methyltransferases (PRMTs) [1]. with IC50s of 30, 119, 83, 4 and 5 nM for PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8, respectively [1].
MS023 treatment (48 h exposure) potently and concentration dependently reduced cellular levels of H4R3me2a (IC50 = 9 ± 0.2 nM), PRMT1 is the main contributor to H4R3 (histone H4 arginine 3) asymmetric dimethylation (H4R3me2a) in cells. MS023 (20 h exposure) concentration dependently reduced the H3R2me2a mark in HEK293 cells (IC50 = 56 ± 7 nM), PRMT6 robustly increased endogenous asymmetric dimethylation of H3R2 (histone H3 arginine 2) [1]. MS023 (1µM, 24h) significantly reduced SARS-CoV-2 replication in VeroE6 cells by inhibition of arginine methylation [2]. MS023 (150,175,200µM) for 48 h treated DLD1 and HCT116 cells increased levels of active form of caspase 3 and PARP degradation as representative apoptosis-related proteins [3].
MS023 treatment on mice model of spinal muscular atrophy (SMA) with both 2 mg/kg and 5 mg/kg resulted in significant increase in survival, with the 2 mg/kg dose achieving the best effect (median: 10 days), compared to both untreated (median: 7) and vehicle-treated (median: 6 days) mice. Mice treated with MS023 also showed an improvement in the disease-associated weight loss [4]. Once-daily dosing of 60 mg kg-1 MS023 initiated in mice with palpable tumors significantly reduced tumor growth and final tumor weight on MDA-MB-468 xenograft mice [5].
References:
[1]. Eram M S, Shen Y, Szewczyk M M, et al. A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases[J]. ACS chemical biology, 2016, 11(3): 772-781.
[2]. Cai T, Yu Z, Wang Z, et al. Arginine methylation of SARS-Cov-2 nucleocapsid protein regulates RNA binding, its ability to suppress stress granule formation, and viral replication[J]. Journal of Biological Chemistry, 2021, 297(1).
[3]. Lim Y, Lee J Y, Ha S J, et al. Proteome-wide identification of arginine methylation in colorectal cancer tissues from patients[J]. Proteome Science, 2020, 18(1): 1-11.
[4]. Kordala A J, Ahlskog N, Hanifi M, et al. Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice[J]. bioRxiv, 2022.
[5]. Wu Q, Nie D Y, Ba-Alawi W, et al. PRMT inhibition induces a viral mimicry response in triple-negative breast cancer[J]. Nature Chemical Biology, 2022: 1-10.