title: SNX-25a, a novel Hsp90 inhibitor, inhibited human cancer growth more potently than 17-AAG.
abstract: 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a typical Hsp90 inhibitor derived from geldanamycin (GA), has entered Phase III clinical trials for cancer therapy. However, it has several significant limitations such as poor solubility, limited bioavailability and unacceptable hepatotoxicity. In this study, the anticancer activity and mechanism of SNX-25a, a novel Hsp90 inhibitor, was investigated comparing with that of 17-AAG. We showed that SNX-25a triggered growth inhibition more sensitively than 17-AAG against many human cancer cells, including K562, SW-620, A375, Hep-2, MCF-7, HepG2, HeLa, and A549 cell lines, especially at low concentrations (<1 μM). It showed low cytotoxicity in L-02, HDF and MRC5 normal human cells. Compared with 17-AAG, SNX-25a was more potent in arresting the cell cycle at G2 phase, and displayed more potent effects on human cancer cell apoptosis and Hsp90 client proteins. It also exhibited a stronger binding affinity to Hsp90 than 17-AAG using molecular docking. Considering the superiority effects on Hsp90 affinity, cell growth, cell cycle, apoptosis, and Hsp90 client proteins, SNX-25a is supposed as a potential anticancer agent that needs to be explored in detail.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China; Department of Pathology, Jinan University, Guangzhou 510632, China; School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Du
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Dane
authors.initials: D
authors.lastname: Huang
authors.affiliation: School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Kaisheng
authors.initials: K
authors.lastname: Liu
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Jinan University, Guangzhou 510632, China. Electronic address: tzxy@jnu.edu.cn.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China. Electronic address: twang-yf@163.com.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin
keywords: 17-AAG; Apoptosis; Cell growth; Client proteins; Hsp90; SNX-25a