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

被引：10

作者：

Che, Jinxin ^{[1
]}

Jin, Zegao ^{[1
]}

Yan, Fangjie ^{[2
,3
]}

You, Jieqiong ^{[2
]}

Xie, Jiangfeng ^{[1
]}

Chen, Binhui ^{[1
]}

Cheng, Gang ^{[4
]}

Zhu, Hong ^{[2
,5
]}

He, Qiaojun ^{[1
,2
,3
,5
]}

Hu, Yongzhou ^{[1
]}

Yang, Bo ^{[2
,3
]}

Cao, Ji ^{[2
,3
,5
]}

Dong, Xiaowu ^{[1
,3
,5
]}

机构：

[1] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China

[2] Zhejiang Univ, Coll Pharmaceut Sci, Inst Pharmacol & Toxicol, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China

[3] Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China

[4] Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Peoples R China

[5] Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 12期

基金：

中国国家自然科学基金;

关键词：

TUMOR-METASTASIS; SUPPRESSOR GENE; HYPOXIA; INVASION; PROMOTES;

D O I：

10.1021/acs.jmedchem.1c00586

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：8621 / 8643

页数：23

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