Discovery of novel imidazo[2,1-b][1,3,4]thiadiazole analogs as fluorescent SHP2 inhibitors.

Overexpression or gene mutation of SHP2 is closely linked with a variety of cancers and has been identified as a crucial anticancer target. The fluorescent molecules have the potential for promoting novel SHP2 inhibitors development by visualizing its tissue distribution and biological behavior information. In the work, we designed and synthesized a series of imidazo[2,1-b][1,3,4]thiadiazole derivatives. Among them, several imidazo[2,1-b][1,3,4]thiadiazole derivatives exhibited potent inhibitory activities against SHP2. The representative compound 4q demonstrated significant potency against SHP2 with IC of 2.89 ± 1.60 μM. Moreover, biological assays verified that it was efficacious in blocking the SHP2-mediated p-ERK signaling pathway and inhibited MV4-11 cell proliferation in vitro with IC of 7.90 ± 0.75 μM. In addition, compound 4q showed green fluorescence imaging in HeLa cells and zebrafish. This study provided a feasible way to develop novel fluorescent SHP2 inhibitors.