Discovery of Pyrazolo[1,5-a]pyridine derivatives as potent RET inhibitors for the treatment of human thyroid and lung Cancer.

Rearranged during transfection (RET) kinase mutations are frequently observed in the context of human thyroid and lung cancer treatment. Moreover, a considerable amount of effort has been dedicated by the scientific community to the identification of highly potent and selective RET inhibitors. In this study, we identified a series of pyrazolo[1,5-a]pyridine derivatives, and compound 9 as a candidate drug that targets both wild-type (wt) RET and RETV804M by structure-activity relationship (SAR) study. In addition, 9 exhibited remarkable antitumor activity at a dose of 10 mg/kg/day, indicating that it completely hindered the growth of tumors induced by BAF3-KIF3B-RET-WT xenografts. In summary, 9 can be demonstrated to act as a potential RET inhibitor, as well as a treatment for RET-related cancers.