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

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

  • Bioorg Med Chem Lett. 2026 Mar 26:137:130629. doi: 10.1016/j.bmcl.2026.130629.
Lin Pan 1,  Yangxiao Hu 2,  Fuxing Tan 2,  Qinghong Fang 2,  Junyue Chen 2,  Yingjun Zhang 2,  Wanqing Wu 3,  Hongming Xie 4
Affiliations

Affiliations

  • 1 Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China.
  • 2 State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Company, Ltd., Dongguan 523871, China.
  • 3 Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China. Electronic address: cewuwq@scut.edu.cn.
  • 4 State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Company, Ltd., Dongguan 523871, China. Electronic address: xiehongming@hec.cn.
PMID: 41903767 DOI: 10.1016/j.bmcl.2026.130629
Abstract

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.

Keywords

Kinase inhibitors; Lung cancer; Rearranged during transfection Pyrazolo[1,5-a]pyridine.

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