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Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases. In the present study, the pharmacophore models built based on the commercial drug tofacitinib and the JAK2/3 proteins derived from molecular dynamics (MD) trajectories were employed to search for a dual potent JAK2/3 inhibitor by a pharmacophore-based virtual screening of 54 synthesized pyrazolone derivatives from an in-house data set. Twelve selected compounds from the virtual screening procedure were then tested for their inhibitory potency against both JAKs in the kinase assay. The in vitro kinase inhibition experiment indicated that compounds 3h, TK4g, and TK4b can inhibit both JAKs in the low nanomolar range. Among them, the compound TK4g showed the highest protein kinase inhibition with the half-maximal inhibitory concentration (IC 50 ) value of 12.61 nM for JAK2 and 15.80 nM for JAK3. From the MD simulations study, it could be found that the sulfonamide group of TK4g can form hydrogen bonds in the hinge region at residues E930 and L932 of JAK2 and E903 and L905 of JAK3, while van der Waals interaction also plays a dominant role in ligand binding. Altogether, TK4g, found by virtual screening and biological tests, could serve as a novel therapeutical lead candidate.

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases