A highly selective 1,2-dihydroquinoxaline derivative as a potent PRMT5-MTA complex inhibitor

Protein arginine methyltransferase 5 (PRMT5) is a promising therapeutic target in oncology. However, first-generation PRMT5 inhibitors failed in clinical trials due to dose-limiting hematologic toxicity, likely resulting from non-selective inhibition of PRMT5 in normal cells. PRMT5 synthetic lethal inhibitors, which selectively target the PRMT5-methylthioadenosine (MTA) complex in MTAP-deletion cancer cells, offer a strategy to improve the therapeutic index. We designed and synthesized a series of novel PRMT5 synthetic lethal inhibitors based on a 1,2-dihydroquinoxaline core. Among them ZC-A2 and (+)ZC-A5 exhibited potent inhibitory activity against the PRMT5-MTA complex, with IC₅₀ values of 0.88 ± 0.06 nM and 0.86 ± 0.15 nM, respectively. Both compounds demonstrated high selectivity, effectively suppressing symmetric dimethylarginine (SDMA) levels in HCT116 MTAP-deleted cells (IC₅₀ = 3.94 ± 1.55 nM and 6.35 ± 0.67 nM, respectively) while showing minimal effect in HCT116 MTAP-wild-type cells. Additionally, (+)ZC-A5 exhibited favorable pharmacokinetic profiles with rapid oral absorption. These findings identify (+)ZC-A5 as a promising lead compound for the development of novel PRMT5-MTA complex inhibitors.