PRMT5-IN-19 (Compound 41) is a potent, orally active PRMT5 inhibitor, exhibiting selectivity towards the SAM-binding pocket of PRMT5 with IC50 values of 23.9 nM (radioactive biochemical assay) and 47 nM (AlphaLISA assay). It effectively blocks methyltransferase activity and demonstrates high specificity against other PRMTs and PKMTs, exerting anti-proliferative effects through apoptosis induction and holding potential in cancer-related research [1].

PRMT5:23.9 nM, PRMT4:>20 μM, PRMT1:3.252 μM

PRMT5-IN-19, denoted as compound 41 and administered over a period of 5 days, demonstrates potent anti-proliferative activity on A375 cells, with an IC50 value of 1.36 μM [1]. This compound exhibits remarkable selectivity for PRMT5, evidenced by an IC50 value of 23.9 nM, favoring it over other histone methyltransferases (PRMT1 and PRMT4) and PKMTs (EZH2, NSD2, MLL1, and MLL4) [1]. It operates by targeting the SAM-binding pocket in PRMT5 [1]. Furthermore, PRMT5-IN-19 has been shown to effectively inhibit the proliferation of various cancer cell lines, including A-375, CHL-1, SNU-423, SNU-449, MDA-MB-231, MDA-MA-453, MV-4-11, and MOLM13, with IC50 values ranging from 1.08 to 3.45 μM over a treatment duration of 4-5 days [1]. Notably, it suppresses arginine symmetrical dimethylation in A375 cells and prompts apoptosis in a concentration-dependent manner, consequently inhibiting cell proliferation when applied at concentrations of 0-4 μM for 48 hours [1]. This synthesis is underscored by cell proliferation assays and western blot analyses, which corroborate the compound's efficacy in dosages up to 10 μM over 5 days and its mechanism of action through dose-dependent inhibition of arginine symmetrical dimethylation in A-375 cells [1].

PRMT5-IN-19 (Compound 41, A375 xenograft model, 75 mg/kg/d, p.o., 19 days) demonstrates favorable pharmacokinetic properties and significant antitumor efficacy, without causing notable body weight loss or visible toxicity [1]. In the A375 cell-derived nude mouse xenograft model, a dosage of 75 mg/kg/day for 19 days via oral administration resulted in a tumor growth inhibition rate of 73% by inhibiting PRMT5 methyltransferase activity. Pharmacokinetic analysis in rats and mice indicated the compound has specific PK parameters: in rats, following intravenous administration (3 mg/kg) and oral administration (10 mg/kg), with respective T 1/2 of 2.58 h and 7.51 h, C max of 152 ng/mL and 8.22 ng/mL, AUC 0-inf of 173 h ng/mL and 36.6 h ng/mL, clearance of 310 mL/min/kg and 65.3 mL/min/kg, volume of distribution (V ss) of 62.5 L/kg and 7.25 L/kg, and bioavailability (F) of 2.95% and 27.7% [1].