As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent Hsp90 inhibitor. Target inhibitory activity result showed that one compound dubbed as 12-1 exhibited strong inhibitory activity against Hsp90 with an IC₅₀ value of 9 nM. In tumor cell viability experiment, compound 12-1 robustly repressed the proliferation against six human tumor cells with IC₅₀ values all in nanomolar range scoring over VER-50589 and geldanamycin. 12-1 was able to induce apoptosis of tumor cells and arrest the tumor cell cycle in G0/G1 phase. Meanwhile, western blot results showed that 12-1 could significantly downregulated the expression of two Hsp90 client proteins CDK4 and HER2. Finally, molecular dynamic simulation showed that compound 12-1 could fit well with ATP binding site on N-terminal of Hsp90.

2023-03-01·Antiviral Research

Antiviral activity of the HSP90 inhibitor VER-50589 against enterovirus 71

Article

作者: Huang, Chaolin ; Deng, Danchun ; Wang, Qian ; Lin, Binbin ; Qiu, Fang ; Li, Zhengnan ; Zhu, Guangyan ; Zhang, Dingyu ; Hu, Xujuan ; Yang, Qingyu ; Wu, Chengyuan

Enterovirus 71 (EV71) is the major pathogen responsible for hand, foot, and mouth disease (HFMD) outbreaks; to date, there is no specific anti-EV71 agent. HSP90 is a crucial host factor for the viral life cycle and an ideal therapeutic target for limiting viral proliferation. However, the specific role of HSP90 in EV71-related signaling pathways and anti-EV71 agents targeting HSP90 remains unclear. This study aimed to verify the role of HSP90 in signaling pathways involved in EV71 replication and investigate the antiviral effects of a small molecule of VER-50589, a potent HSP90 inhibitor, against EV71 both in vitro and in vivo. Viral plaque assay, western blotting, and qPCR results showed that VER-50589 diminished the plaque formation induced by EV71 and inhibited EV71 mRNA and protein synthesis. A single daily dose of VER-50589 treatment significantly improved the survival rate of EV71-infected mice (p < 0.005). Interestingly, VER-50589 also exhibits activities against a series of human enteroviruses, including Coxsackievirus B3 (CVB3), Coxsackievirus B4-5 (CVB4-5), Coxsackievirus B4-7 (CVB4-7), and Echovirus 11 (Echo11). EV71 infection activated the AKT and ERK signaling pathways, and phosphorylation of AKT and RAF/MEK/ERK was weakened by VER-50589 administration. Thus, VER-50589 exhibits robust antiviral activity by inhibiting HSP90 and mediating the AKT and RAF/MEK/ERK signaling pathways. Considering that there are no effective antivirals or vaccines for the prevention and cure of HFMD in a clinical setting, the development of an anti-EV71 agent would be a straightforward and feasible therapeutic approach.

2007-04-01·Molecular Cancer Therapeutics2区 · 医学

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

2区 · 医学

Article

作者: Barril, Xavier ; Raynaud, Florence ; Jones, Keith ; Surgenor, Allan ; Brough, Paul A. ; Hardcastle, Anthea ; Boxall, Kathy ; Eccles, Sue ; James, Karen ; Dymock, Brian ; Wright, Lisa ; Cansfield, Julie E. ; Sharp, Swee Y. ; Matthews, Thomas P. ; Box, Gary ; McDonald, Edward ; Kalusa, Andrew ; Aherne, Wynne ; Foloppe, Nicolas ; Hubbard, Roderick E. ; Prodromou, Chrisostomos ; Powers, Marissa V. ; Pearl, Laurence ; Hayes, Angela ; Drysdale, Martin ; Holmes, Joanna L. ; Workman, Paul ; Cheung, Kwai-Ming J.

AbstractAlthough the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (Kd) of VER-50589 was 4.5 ± 2.2 nmol/L compared with 78.0 ± 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC50 of 21 ± 4 nmol/L for VER-50589 compared with 47 ± 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI50 values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 ± 15 and 685 ± 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI50 for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors. [Mol Cancer Ther 2007;6(4):1198–211]

100 项与 VER-50589 相关的药物交易

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