Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors

Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitocho...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-09, Vol.60 (17), p.7569-7578
Main Authors: Park, Hye-Kyung, Jeong, Hanbin, Ko, Eunhwa, Lee, Geumwoo, Lee, Ji-Eun, Lee, Sang Kwang, Lee, An-Jung, Im, Jin Young, Hu, Sung, Kim, Seong Heon, Lee, Ji Hoon, Lee, Changwook, Kang, Soosung, Kang, Byoung Heon
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cell Death - drug effects
Cell Line, Tumor
Crystallography, X-Ray
HeLa Cells
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Humans
Mice, Nude
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - pathology
Molecular Docking Simulation
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - pharmacology
Pyrazoles - therapeutic use
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
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Summary:Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00978