Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant

  • Eur J Med Chem. 2020 Dec 1;207:112755. doi: 10.1016/j.ejmech.2020.112755.
Xiaoyang Li  1 ,  Jingyi Su  1 ,  Yanru Yang  1 ,  Wenhua Lian  1 ,  Zhou Deng  1 ,  Zaiyou Yang  1 ,  Guyue Chen  1 ,  Baoding Zhang  1 ,  Chao Dong  1 ,  Xueyan Liu  1 ,  Li Li  1 ,  Zheng Wang  1 ,  Zhiyu Hu  1 ,  Qingyan Xu  1 ,  Xianming Deng  2
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address: [email protected].
PMID: 32882611 DOI: 10.1016/j.ejmech.2020.112755
Abstract

The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung Cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid Cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of 9x representing a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors. 9x exhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50 of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50 of 4 nM. More importantly, 9x also showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative Cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective 'on-target' effect. In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.

Keywords
CCDC6-RET; KIF5B-RET; Non-small cell lung cancer; RET inhibitor; Structure-activity relationship.
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