X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response.
Heat shock protein 90 (HSP90) is essential for cancer cells to assist the function of various oncoproteins, and it has been recognized as a promising target in cancer therapy. Although the HSP90 inhibitors in clinical trials have shown encouraging clinical efficacy, these agents induce heat shock response (HSR), which undermines their therapeutic effects. In this report, we detailed the pharmacologic properties of 4-(2-((1H-indol-3-yl)methylene)hydrazinyl)-N-(4-bromophenyl)-6-(3,5- dimethyl-1H -pyrazol-1-yl)-1,3,5-triazin-2-amine (X66), a novel and potent HSP90 inhibitor. X66 binds to the N-terminal domain in a different manner from the classic HSP90 inhibitors. Cellular study showed that X66 depleted HSP90 client proteins, resulted in cell cycle arrest and apoptosis, and inhibition of proliferation in cancer cell lines. X66 did not activate heat shock factor-1 (HSF-1) or stimulate transcription of HSPs. Moreover, the combination of X66 with HSP90 and proteasome inhibitors yielded synergistic cytotoxicity which was involved in X66-mediated abrogation of HSR through inhibition of HSF-1 activity. The intraperitoneal administration of X66 alone depleted client protein and inhibited tumor growth, and led to enhanced activity when combined with celastrol as compared to either agent alone in BT-474 xenograft model. Collectively, the HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Zhixin
Z
Zhao
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Jianming
J
Zhu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Haitian
H
Quan
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Guimin
G
Wang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Bo
B
Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Weiliang
W
Zhu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Chengying
C
Xie
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Liguang
L
Lou
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D006835:Hydrazones; D014227:Triazines; C000625863:X66 compound
HSF-1; HSP90; X66; celastrol; heat shock response