Wang Xiao, Wang Shaoxiang, Liu Yuting, Huang Dane, Zheng Kai, Zhang Yi, Wang Xiaoyan, Liu Qiuying, Yang Depo, Wang Yifei
Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guangdong 510095, P.R. China.
Oncol Rep. 2015 Jan;33(1):230-8. doi: 10.3892/or.2014.3552. Epub 2014 Oct 20.
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.
SNX - 2112是一种新型的Hsp90 2 - 氨基苯甲酰胺抑制剂，此前显示出广泛的抗癌活性。然而，由于在一项I期研究中发现的眼部毒性，后续开发已停止。SNX - 7081是另一种密切相关的Hsp90抑制剂，其侧链为吲哚而非吲唑，最近引起了关注。本研究的目的是以SNX - 2112为参照，研究SNX - 7081对11种细胞系的抗癌作用及其相关机制。使用MTT法测定细胞毒性作用，采用流式细胞术检测细胞凋亡。结果显示，在八分之六的人类癌细胞系中，SNX - 7081比SNX - 2112具有更好的抑制作用，平均IC50为1 μM。这两种抑制剂对L - 02、HDF和MRC5正常人细胞的细胞毒性较低（IC50>50 μM），并且与正常细胞类似，使癌细胞停滞在G2/M期。与SNX - 2112相比，SNX - 7081在六分之四的人类癌细胞系中对细胞凋亡表现出更强的作用，并且在下调Hsp90客户蛋白方面更具活性。此外，在分子对接实验中，SNX - 7081对Hsp90的结合亲和力比SNX - 2112更强。考虑到在大多数人类癌细胞中，SNX - 7081在Hsp90亲和力、细胞生长、细胞凋亡和Hsp90客户蛋白方面具有更优异的作用，新型SNX - 7081可能是SNX - 2112的一个有前景的替代品，值得进一步评估。
