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 (Compound 41, 5 days) has strong anti-proliferative effects against the A375 cell with an IC 50 value of 1.36 μM [1]. PRMT5-IN-19 shows higher selectivity for PRMT5 ( IC 50 value of 23.9 nM) than other histone methyltransferases (PRMT1 and PRMT4), and PKMTS (EZH2, NSD2, MLL1, and MLL4) [1]. PRMT5-IN-19 binds with the SAM-binding pocket in PRMT5 [1]. PRMT5-IN-19 (4-5 days) Inhibits proliferation of multiple cancer cell lines (A-375, CHL-1, SNU-423, SNU-449, MDA-MB-231, MDA-MA-453, MV-4-11, MOLM13) with IC 50 value ranging from 1.08 to 3.45 μM [1]. PRMT5-IN-19 inhibits arginine symmetrical dimethylation in A375 cells [1]. PRMT5-IN-19 (0-4 μM, 48 h) suppresses A375 cell proliferation by inducing apoptosis in a concentration-dependent manner [1]. Cell Proliferation Assay [1] Cell Line: A-375, CHL-1, SNU-423, SNU-449, MDA-MB-231, MDA-MA-453, MV-4-11, MOLM13 Concentration: 0-10 μM Incubation Time: 5 days Result: Inhibited proliferation of multiple cancer cell lines with IC 50 value ranging from 1.08 to 3.45 μM. Western Blot Analysis [1] Cell Line: A-375 cells Concentration: 0.5, 1, 2, 4,8 μM Incubation Time: 48 h. Result: Inhibited arginine symmetrical dimethylation in a dose-dependent manner.

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