Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis
| Autor: | Jieqiong You, Hong Zhu, Bo Yang, Zegao Jin, Jinxin Che, Fangjie Yan, Ji Cao, Binhui Chen, Qiaojun He, Jiangfeng Xie, Yongzhou Hu, Xiaowu Dong, Gang Cheng |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Phenotypic screening Aminopyridines Antineoplastic Agents 01 natural sciences Metastasis Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cell Movement In vivo Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans Structure–activity relationship Neoplasm Metastasis 030304 developmental biology Mice Inbred BALB C 0303 health sciences Molecular Structure biology Chemistry Intracellular Signaling Peptides and Proteins medicine.disease 0104 chemical sciences Ubiquitin ligase 010404 medicinal & biomolecular chemistry Cell culture Guanosine diphosphate Cancer cell biology.protein Cancer research Molecular Medicine Female Signal Transduction |
| Zdroj: | Journal of Medicinal Chemistry. 64:8621-8643 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00586 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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