title: Comparative effects of SNX-7081 and SNX-2112 on cell cycle, apoptosis and Hsp90 client proteins in human cancer cells.
abstract: SNX-2112, a novel 2-aminobenzamide inhibitor of Hsp90, previously showed a broad spectrum of anticancer activity. However, subsequent development has been discontinued due to ocular toxicity as identified in a phase I study. SNX-7081, another closely related Hsp90 inhibitor with a side chain of indole instead of indazole, has recently attracted attention. The aim of the present study was to investigate the anticancer effects of SNX-7081 in eleven cell lines, as well as the mechanisms involved, with SNX-2112 serving as a reference. The cytotoxic effects were determined using an MTT assay and apoptosis was measured using flow cytometry. The results showed that SNX-7081 exerted better inhibitory effects than SNX-2112 in six eighths of the human cancer cell lines, with an average IC50 of 1 µM. The two inhibitors exerted low cytotoxicity in L-02, HDF and MRC5 normal human cells (IC50 >50 µM), and arrested cancer cells at the G2/M phase in a similar manner to normal cells. Compared with SNX-2112, SNX-7081 exhibited more potent effects on cell apoptosis in four sixths of the human cancer cell lines, and was more active in the downregulation of Hsp90 client proteins. In addition, SNX-7081 exhibited a stronger binding affinity to Hsp90 than SNX-2112 in molecular docking experiments. Considering the superior effects against Hsp90 affinity, cell growth, apoptosis, and Hsp90 client proteins in a majority of human cancer cells, the novel SNX-7081 may be a promising alternative to SNX-2112, which merits further evaluation.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guangdong 510095, P.R. China.
authors.forename: Dane
authors.initials: D
authors.lastname: Huang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. 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, Guangdong 510632, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Depo
authors.initials: D
authors.lastname: Yang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112; C535175:SNX-7081