Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure

被引：26

作者：

Wang, Lun ^{[1
,2
]}

Zheng, Yunhua ^{[1
,2
]}

Li, Dan ^{[1
,2
]}

Yang, Jianhong ^{[1
,2
]}

Lei, Lei ^{[1
,2
]}

Yan, Wei ^{[1
,2
]}

Zheng, Wei ^{[1
,2
]}

Tang, Minghai ^{[1
,2
]}

Shi, Mingsong ^{[1
,2
]}

Zhang, Ruijia ^{[1
,2
]}

Cai, Xiaoying ^{[1
,2
]}

Ni, Hengfan ^{[3
]}

Ma, Xu ^{[1
,2
]}

Li, Na ^{[1
,2
]}

Hong, Feng ^{[1
,2
]}

Ye, Haoyu ^{[1
,2
]}

Chen, Lijuan ^{[1
,2
]}

机构：

[1] Sichuan Univ, State Key Lab Biotherapy, Collaborat Innovat Ctr Biotherapy, West China Hosp, Chengdu 610041, Peoples R China

[2] Sichuan Univ, Canc Ctr, West China Hosp, Chengdu 610041, Peoples R China

[3] Chengdu Univ Tradit Chinese Med, Sch Pharm, Minist Educ,Breeding Base Systemat Res Dev & Util, State Key Lab,Key Lab Standardizat Chinese Herbal, Chengdu 611137, 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：

COLCHICINE; COMBINATION; PROTEIN; CANCER; AGENTS; POLYMERIZATION; MECHANISM; INSIGHT; PROVIDE; COMPLEX;

D O I：

10.1021/acs.jmedchem.0c01961

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of beta-tubulin and its morpholine group lies close to alpha-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with alpha-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, 8a exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved in vivo antitumor effects. The X-ray crystal structure suggested that 8a both bound to the colchicine site and extended into the interior of alpha-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.

引用

页码：8127 / 8141

页数：15

共 35 条

[1] New Ligands of the Tubulin Colchicine Site Based on X-Ray Structures [J].