JAK3-IN-20

JAK3-IN-20 is an orally active, selective JAK3 inhibitor with an IC50 of 0.7473 nM. It forms a covalent bond with JAK3Cys909 and competitively occupies the ATP catalytic site, blocking activation of the JAK-STAT pathway. JAK3-IN-20 effectively inhibits migration, proliferation, and tumor growth in Bortezomib-resistant cancer cells, and induces dose-dependent apoptosis (apoptosis). It is applicable for research on Bortezomib-resistant multiple myeloma.

JAK3:0.7473 nM

JAK3-IN-20 (Compound 7n), administered at 60 mg/kg via gavage once daily for 21 consecutive days, demonstrates tumor growth inhibition in a bortezomib-resistant multiple myeloma xenograft model, with no significant weight loss observed.

JAK3-IN-20 (Compound 7n) effectively inhibits purified JAK3 protein with an IC50 value of 0.7473 nM. At a concentration of 5 nM, it demonstrates high selectivity for JAK3 with a 96.87% inhibition rate, exhibiting moderate inhibition towards JAK2 and TYK2, and no significant activity on JAK1. Over a period of 72 hours, JAK3-IN-20 strongly inhibits the proliferation of Bortezomib-resistant KM3 multiple myeloma cells, with an IC50 of 0.245 μM, and affects the proliferation of KM3, BaF3-JAK3, Raji, Paca-02, H1975, HK-2, and LX-2 cells, with IC50 values ranging from 0.211 to 4.317 μM. At concentrations of 0.3125-5.0 μM over 48 hours, it induces dose-dependent apoptosis and G2/M phase cell cycle arrest in Bortezomib-resistant KM3 multiple myeloma cells. Moreover, at 78.13-312.5 nM for 48 hours, JAK3-IN-20 concentration-dependently inhibits the migration of these resistant cells. It also upregulates the pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2 in a dose-dependent manner at concentrations of 0.3125-5.0 μM over 48 hours. Additionally, JAK3-IN-20 inhibits the phosphorylation of STAT5 in Bortezomib-resistant KM3 multiple myeloma cells in a dose-dependent manner at concentrations of 15.6 nM-4 μM for 1-72 hours.