Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis

  • J Med Chem. 2021 Jun 24;64(12):8621-8643. doi: 10.1021/acs.jmedchem.1c00586.
Jinxin Che  1 ,  Zegao Jin  1 ,  Fangjie Yan  2  3 ,  Jieqiong You  2 ,  Jiangfeng Xie  1 ,  Binhui Chen  1 ,  Gang Cheng  4 ,  Hong Zhu  2  5 ,  Qiaojun He  1  2  3  5 ,  Yongzhou Hu  1 ,  Bo Yang  2  3 ,  Ji Cao  2  3  5 ,  Xiaowu Dong  1  3  5
Affiliations
  • 1. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 2. Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 3. Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, P. R. China.
  • 4. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311402, P. R. China.
  • 5. Cancer Center, Zhejiang University, Hangzhou 310058, P. R. China.
PMID: 34060833 DOI: 10.1021/acs.jmedchem.1c00586
Abstract

The gain of cell motility is an essential prerequisite for Cancer metastasis. The ubiquitin Ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of Cancer cells. Moreover, compound 4 exhibited a promising in vivo Anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of Cancer metastasis.

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