Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 12, Pages 8621-8643Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00586
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Funding
- Key R&D Program of Zhejiang Province
- National Natural Science Foundation of China
- National Natural Science Foundation for Distinguished Young Scholar of China
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The compound 4 was identified as a WSB1 degrader, inhibiting the migration capacity of WSB1-overexpressing cells and showing promising anticancer metastatic effects in vivo.
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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