2. Academic Validation
  3. Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

  • J Med Chem. 2022 Nov 24;65(22):15374-15390. doi: 10.1021/acs.jmedchem.2c01346.
Shingpan Chan 1,  Yunong Zhang 1,  Jie Wang 1,  Qiuchun Yu 1,  Xia Peng 2,  Jian Zou 1,  Licheng Zhou 3,  Li Tan 1,  Yunxin Duan 1,  Yang Zhou 1,  Hoon Hur 4,  Jing Ai 2,  Zhen Wang 3,  Xiaomei Ren 3,  Zhang Zhang 1,  Ke Ding 1 3 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 4 Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si 16499, Gyeonggi-do, Republic of Korea.
  • 5 The First Affiliated Hospital (Huaqiao Hospital), Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 36358010 DOI: 10.1021/acs.jmedchem.2c01346
Abstract

The receptor tyrosine kinase Axl is a promising target for Anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective Axl kinase inhibitors. One of the representative compounds, 6li, potently inhibited Axl enzymatic activity with an IC50 value of 1.6 nM, and tightly bound with Axl protein with a Kd value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited Axl signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-β1-induced epithelial-mesenchymal transition, and dose-dependently impeded Cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast Cancer 4T1 cells. Taken together, this study provides a new potent and selective Axl Inhibitor for further Anticancer drug discovery.

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