JAK/HDAC-IN-2, a potent 2-amino-4-phenylaminopyrimidine dual-target inhibitor, effectively suppresses JAK1/2 and HDAC3/6 at nanomolar concentrations. This compound exhibits proapoptotic properties, inhibits histone deacetylation, and impedes STAT3 phosphorylation, demonstrating notable antiproliferative activity against various hematological malignancies and solid tumors [1].

JAK1:27.15 nM, JAK3:594.8 nM, TYK2:414.4 nM, HDAC2:303 nM, HDAC3:58.7 nM, HDAC6:4.44 nM, HDAC10:116.1 nM, HDAC11:724.4 nM, HDAC7:>10000 nM, JAK2:5.32 nM, HDAC:170 nM, HDAC1:340 nM, HDAC5:>10000 nM, HDAC8:>10000 nM, HDAC9:>10000 nM, HDAC4:>10000 nM

JAK/HDAC-IN-2 exhibited potent antiproliferative effects against K562, HL-60, and HEL cell lines with IC50 values of 1.87, 2.26, and 0.33 μM, respectively; it also inhibited the proliferation of solid tumor cell lines MCF-7, HeLa, A549, and PC-3 with IC50 values of 1.83, 2.88, 0.73, and 2.52 μM [1]. Additionally, JAK/HDAC-IN-2 demonstrated excellent pro-apoptotic activity in HEL cells and moderate pro-apoptotic activity in A549 cells at a concentration of 1.5 μM over 24 hours [1]. The compound effectively suppressed histone deacetylation and STAT3 phosphorylation in hematological malignancy HEL cells and solid tumor A549 cells at the same concentration and duration by inhibiting HDAC and JAK pathways [1].

JAK/HDAC-IN-2 (Compound 21; 50 mg/kg; intraperitoneal injection; once daily; for 18 consecutive days) demonstrated effective antitumor activity in vivo against hematologic malignancy HEL and solid tumor A549 [1]. The pharmacokinetic parameters of LSD1-IN-14 in male Sprague-Dawley rats were as follows [1]: IV (3 mg/kg) and PO (15 mg/kg) yielded Tmax values of 2.912 hours and Cmax levels at 93.328 ng/mL, respectively. AUC0-t was 656.241 ng/mL*h for IV and 745.249 ng/mL*h for PO administration. The t1/2 was 0.128 hours for IV and 2.084 hours for PO, with clearance (CL) of 4.571 L/kg*h IV and 4.56 L/kg*h PO, and a steady-state volume of distribution (Vss) of 0.845 L/kg. The oral bioavailability (F) was determined to be 22.71%.