Virtual Screening For Dual-inhibitors Of STAT3and STAT5

Although molecularly targeted therapy with Imatinib has improved treatments ofCML, clinical resistance gradually develops in patients with accelerated or blast phaseCML. The inability of Imatinib to cure CML suggests that inactivation of BCR-ABLkinase activity alone is not sufficient to control the disease. Aberrant STAT signalingand constitutive STAT5or STAT3activation were frequently found in both acute andchronic leukemia. Experimental evidences suggested that constitutive activations ofSTAT5and STAT3were associated with Imatinib resistance on leukemia cells. As aresult, targeting to the SH2domains of STAT5and STAT3may provide a novelstrategy for treating the Imatinib-resistant CML.Here, a rational approach using molecular dockings and molecular dynamicssimulations was applied to screen a set of~1500compounds for dual inhibitors ofSTAT5and STAT3SH2domains. Through the virtual screening, three top hits areobtained, which are compound660,304and561. Results showed that the threepredicted dual-inhibitors are well fitted within the two binding domains and showedimproved STAT5and STAT3SH2inhibitory activity compared to the positivecontrols. The binding affinities for compound660with STAT5and STAT3SH2domain are-20.85and-14.33kcal mol-1respectively, much lower than that of thepositive controls. Moreover, the detailed interactions analysis including structurebased dynamics, H-bond analysis, and energy decompositions of three inhibitors withtwo targets provides us insights into the design of future STAT5/STAT3SH2dual-inhibitors.