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.
基金：
The authors gratefully acknowledge financial support from the Ministry of
Science and Technology of China (2015CB910304 to Y.Z.); the National
Natural Science Foundation of China (81625022, 91853205, 81821005 to
C.L., 21820102008 to H.J. and 31270830 and 21572038 to Y.D); the Chinese
Academy of Science grant (XDA12020353 to C.L.), K. C. Wong Education
Foundation to C.L., the National Science and Technology Major
Project (2018ZX09711002 to C.L.), Science and Technology Commission
of Shanghai Municipality (18431907100 to H.J. and 19XD1404700 to C.L.);
the Key Project of High-level University Construction of Guangzhou University
of Chinese Medicine (Nos. XK2018019 and YN2015MS03 to B.L.).
第一作者机构：[1] Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Peoples R China
通讯作者：
通讯机构：[1] Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Peoples R China[*1]Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Peoples R China[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China[*2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China[3] Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China[*3]Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China[4] Guangzhou Univ Chinese Med, Clin Med Coll 2, Guangzhou 510006, Peoples R China[*4]Guangzhou Univ Chinese Med, Clin Med Coll 2, Guangzhou 510006, Peoples R China[5] Guangzhou Univ Chinese Med, Guangdong Prov Key Lab Clin Res Tradit Chinese Me, Guangzhou 510006, Peoples R China[*5]Guangzhou Univ Chinese Med, Guangdong Prov Key Lab Clin Res Tradit Chinese Me, Guangzhou 510006, Peoples R China[*6]Guangzhou Key Lab Chiral Res Act Components Tradi, Guangzhou 510006, Peoples R China[*7]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[*8]Fujian Med Univ, Coll Pharm, Dept Pharmacol, Fuzhou 350004, Peoples R China[9] Guangzhou Key Lab Chiral Res Act Components Tradi, Guangzhou 510006, Peoples R China[*9]Guizhou Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Huaxi Dist 550025, Guizhou, 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[11] Fujian Med Univ, Coll Pharm, Dept Pharmacol, Fuzhou 350004, Peoples R China[12] Guizhou Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Huaxi Dist 550025, Guizhou, Peoples R China
推荐引用方式(GB/T 7714)：
Sun Zhongya,Zhang Hao,Zhang Yuanyuan,等.Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion[J].ADVANCED SCIENCE.2020,7(14):
工程技术