2. Academic Validation
  3. Discovery of 3,5-diaryl-1H-pyrazol-based ureas as potent RET inhibitors

Discovery of 3,5-diaryl-1H-pyrazol-based ureas as potent RET inhibitors

  • Eur J Med Chem. 2023 May 5;251:115237. doi: 10.1016/j.ejmech.2023.115237.
Kaifu Wu 1,  Rui He 1,  Zongyang Li 2,  Kongxi Qiu 1,  Guorong Xiao 1,  Lijie Peng 1,  Xiangbao Meng 3,  Canhui Zheng 4,  Zhang Zhang 5,  Qian Cai 6
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 2 Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China.
  • 4 School of Pharmacy, Naval Medical University (Second Military Medical University), Shanghai, 200433, China. Electronic address: [email protected].
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. Electronic address: [email protected].
  • 6 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
PMID: 36905915 DOI: 10.1016/j.ejmech.2023.115237
Abstract

Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy. However, the discovery of novel RET inhibitors with high target selectivity and improved safety is still highly desirable. Herein, we reported a class of 3,5-diaryl-1H-pyrazol-based ureas as new RET inhibitors. The representative compounds 17a/b displayed high selectivity to other kinases, and potently inhibited isogenic BaF3-CCDC6-RET cells harboring wild-type, or gatekeeper mutation (V804M). They also displayed moderate potency against BaF3-CCDC6-RET-G810C with solvent-front mutation. Compound 17b showed better pharmacokinetics properties and demonstrated promising oral in vivo antitumor efficacy in a BaF3-CCDC6-RET-V804M xenograft model. It may be utilized as a new lead compound for further development.

Keywords

3,5-Diaryl-1H-pyrazol-baed urea; Inhibitors; Kinase; Rearranged during transfaction (RET); Selectivity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149099
    RET Inhibitor
    RET