Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug
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- Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug
- Hu, Sung; Ferraro, Mariarosaria; Thomas, Ajesh P.; Chung, Jeong Min; Yoon, Nam Gu; Seol, Ji-Hoon; Kim, Sangpil; Kim, Han-Ul; An, Mi Young; Ok, Haewon; Jung, Hyun Suk; Ryu, Ja-Hyoung; Colombo, Giorgio; Kang, Byoung Heon
- Issue Date
- AMER CHEMICAL SOC
- JOURNAL OF MEDICINAL CHEMISTRY, v.63, no.6, pp.2930 - 2940
- 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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