Discovery of Hexahydrofuro[3,2-]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound potently inhibited JAK3 kinase activity with an IC value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3 activating mutation and human leukemia U937 cells harboring JAK3 with IC values of 22.9 and 20.2 nM, respectively. More importantly, showed reasonable pharmacokinetic (PK) properties, and oral administration of at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.