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

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

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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