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. PRMT5-IN-19 exerts anti-proliferative effects through the induction of apoptosis and holds potential in cancer-related research [1].

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) has good PK properties and significant antitumor efficacy, without the obvious loss of body weight and visible toxicity [1]. Animal Model: A375 cell-derived nude mouse xenograft model [1]. Dosage: 75 mg/kg/d Administration: P.o., 19 days Result: Had no effect on the body weight, displayed antitumor efficacy with a tumor growth inhibition (TGI) rate of 73% by inhibiting the methyltransferase activity of PRMT5. Animal Model: Rats and mice [1]. Dosage: 10 mg/kg for p.o., 3 mg/kg for i.v Administration: P.o., i.v. (Pharmacokinetic Analysis) Result: Pharmacokinetic parameters for PRMT5-IN-19 in SD Rats and Mice a,c [1]. species PRMT5-IN-19 T 1/2 (h) C max (ng/mL) 7 (h ng/mL) AUC 0-inf (h ng/mL) CL (mL/min/kg) V ss (L/kg) F (%) rat iv (3 mg/kg)/td> 2.58 152 173 310 62.5 po (10 mg/kg)/td> 7.51 8.22 36.6 65.3 7.25 po (10 mg/kg)/td> 2.95 27.7 120