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  3. Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity

Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity

  • Acta Pharmacol Sin. 2022 Apr;43(4):1046-1058. doi: 10.1038/s41401-021-00737-x.
Chuan-Jing Cheng 1,  Kai-Xin Liu 1,  Man Zhang 1,  Fu-Kui Shen 1,  Li-Li Ye 1,  Wen-Bo Wu 1,  Xiao-Tao Hou 2 3,  Er-Wei Hao 2 3,  Yuan-Yuan Hou 4,  Gang Bai 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China.
  • 2 Collaborative Innovation Center of Research on Functional Ingredients from Agricultural Residues, Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese medicine, Nanning, 530200, China.
  • 3 China-ASEAN Joint Laboratory for International Cooperation in Traditional Medicine Research, Guangxi University of Chinese Medicine, Nanning, 530200, China.
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China. houyy@nankai.edu.cn.
  • 5 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China. gangbai@nankai.edu.cn.
  • 6 China-ASEAN Joint Laboratory for International Cooperation in Traditional Medicine Research, Guangxi University of Chinese Medicine, Nanning, 530200, China. gangbai@nankai.edu.cn.
PMID: 34326484 DOI: 10.1038/s41401-021-00737-x
Abstract

Heat shock protein 90 (HSP90) has been recognized as a crucial target in Cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 μM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

Keywords

CDC37; HSP90; antitumor; chaperone; okicamelliaside.

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