期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 6, 页码 2930-2940出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01420
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资金
- AIRC (Associazione Italiana Ricerca sul Cancro) [IG 20019]
- NTAP (Neurofibromatosis Acceleration Program)
- UNIST research fund (Republic of Korea) [1.190043]
- National Research Foundation of Korea - MSIT (Republic of Korea) [NRF-2018R1A5A1024340, NRF-2016R1A2B2012624, NRF-2018R1D1A1B07045580, NRF-2019M3A9A8065669, NRF-2017R1A2B4003617]
- National Research Foundation of Korea [2019M3A9A8065669] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90 and is overexpressed in many cancer cells. The orthosteric ATP-binding site of TRAP1 has been considered the primary inhibitor binding location, but TRAP1 allosteric modulators have not yet been investigated. Here, we generated and characterized the Hsp90 inhibitor PU-H71, conjugated to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with a C-10 carbon spacer, named SMTIN-C10, to enable dual binding to orthosteric and allosteric sites. In addition to tight binding with the ATP-binding site through the PU-H71 moiety, SMTIN-C10 interacts with the E115 residue in the N-terminal domain through the TPP moiety and subsequently induces structural transition of TRAP1 to a tightly packed closed form. The data indicate the existence of a druggable allosteric site neighboring the orthosteric ATP pocket that can be exploited to develop potent TRAP1 modulators.
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