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Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion

文献类型：期刊论文

作者Sun, Zhongya2; Zhang, Hao3; Zhang, Yuanyuan3; Liao, Liping3,4; Zhou, Wen1,5; Zhang, Fengcai3,6; Lian, Fulin3; Huang, Jing3,4; Xu, Pan3,4; Zhang, Rukang3,4
刊名ADVANCED SCIENCE
出版日期2020-05-13
页码13
关键词anti-metastasis activities crystal structures inhibitors novel pockets rho family proteins
DOI10.1002/advs.202000098
通讯作者Liu, Bo(doctliu@gzucm.edu.cn) ; Liu, Chuanpeng(liucp74@hotmail.com) ; Dang, Yongjun(yongjundang@fudan.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward "undruggable" protein targets.
WOS关键词NUCLEOTIDE EXCHANGE ; RATIONAL DESIGN ; GTPASES ; PROLIFERATION ; DISCOVERY ; ROLES ; RAC1
资助项目Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[31270830] ; National Natural Science Foundation of China[21572038] ; Chinese Academy of Science[XDA12020353] ; K. C. Wong Education Foundation ; National Science and Technology Major Project[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Key Project of High-level University Construction of Guangzhou University of Chinese Medicine[XK2018019] ; Key Project of High-level University Construction of Guangzhou University of Chinese Medicine[YN2015MS03]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:000531850700001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/280257]  
专题新药研究国家重点实验室
通讯作者Liu, Bo; Liu, Chuanpeng; Dang, Yongjun; Luo, Cheng
作者单位1.Guangzhou Univ Chinese Med, Guangdong Prov Key Lab Clin Res Tradit Chinese Me, Guangzhou 510006, Peoples R China
2.Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
5.Guangzhou Univ Chinese Med, Clin Med Coll 2, Guangzhou 510006, Peoples R China
6.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
7.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
8.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
9.Guangzhou Key Lab Chiral Res Act Components Tradi, Guangzhou 510006, Peoples R China
10.Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med,Key Lab Metab & Mol Med, Dept Biochem & Mol Biol,Sch Basic Med Sci,Minist, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Zhongya,Zhang, Hao,Zhang, Yuanyuan,et al. Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion[J]. ADVANCED SCIENCE,2020:13.
APA Sun, Zhongya.,Zhang, Hao.,Zhang, Yuanyuan.,Liao, Liping.,Zhou, Wen.,...&Luo, Cheng.(2020).Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.ADVANCED SCIENCE,13.
MLA Sun, Zhongya,et al."Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion".ADVANCED SCIENCE (2020):13.

入库方式： OAI收割

来源：上海药物研究所

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