JAK3-IN-1

JAK3-IN-1 is a potent, selective and orally active JAK3 inhibitor with an IC₅₀ of 4.8 nM. JAK3-IN-1 shows over 180-fold more selective for JAK3 than JAK1 (IC₅₀ of 896 nM) and JAK2 (IC₅₀ of 1050 nM)^[1]. In Vitro: JAK3-IN-1(Compound 9; 0-5 µM; 3 hours; BMDMs cells) treatment completely inhibits IL-4 induced p-STAT6 at a concentration of 500 nM and only partially inhibits IFNβ-induced p-STAT1 at a concentration of 5.0 μM^[1].
. JAK3-IN-1(Compound 9) most potently inhibits JAK3 and identified fms-related tyrosine kinase 3 (FLT3) and several tyrosine protein kinase (TEC)-family kinases as being potential off-targets. Enzymatic assays using the Z’-lyte or LanthaScreen formats confirmed enzymatic inhibition of FLT3 (IC₅₀ = 13 nM), TTK protein kinase (TTK, IC₅₀ = 49 nM), BLK proto-oncogene (BLK, IC₅₀ = 157 nM) and tyrosine protein kinase TXK (TXK, IC₅₀ = 36 nM). JAK3-IN-1 shows very low inhibition scores for other JAKs and wild-type (WT) EGFR, which is consistent with the over 180-fold higher IC₅₀s against EGFRWT and TYK2 (IC₅₀s =409 nM, > 10000 respectively). JAK3-IN-1 possesses over 165-fold higher IC₅₀s for BTK or ITK (IC₅₀s = 794 and 1070 nM respectively)^[1].
JAK3-IN-1(Compound 9) selectively inhibits the proliferation of JAK3-dependent Ba/F3 cells (IC₅₀ = 69 nM) relative to other JAK-dependent Ba/F3 cells, for which there was no antiproliferative effect at concentrations below 3.0 μM^[1]. In Vivo: JAK3-IN-1(Compound 9) shows reasonable pharmacokinetic properties, with moderate T_1/2 of 1.4 h, area under the curve (AUC) value of 795 ng*hr/mL following a 10 mg/Kg oral dose and good oral bioavailability of 66%. After oral administration with JAK3-IN-1(Compound 9) (75 mpk, QD) for 8 days, the numbers of B or T lymphocytes in the tumor-bearing lungs and spleens of treated mice is not affected, however, the number of NK cells is reduced^[1].