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

Title
Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors
Authors
Park, Hye-KyungJeong, HanbinKo, EunhwaLee, GeumwooLee, Ji-EunLee, Sang KwangLee, An-JungIm, Jin YoungHu, SungKim, Seong HeonLee, Ji HoonLee, ChangwookKang, SoosungKang, Byoung Heon
Ewha Authors
강수성
Issue Date
2017
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link1520-4804JCR Link
Citation
vol. 60, no. 17, pp. 7569 - 7578
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
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.
DOI
10.1021/acs.jmedchem.7b00978
Appears in Collections:
약학대학 > 약학과 > Journal papers
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