Advances in small-molecule inhibitors targeting Hsp90-Cdc37 protein-protein interaction

LIU Fang; SUN Haopeng; YOU Qidong

doi:10.11665/j.issn.1000-5048.20150303

Journal of China Pharmaceutical University > 2015 > 46(3): 272-278. > DOI: 10.11665/j.issn.1000-5048.20150303

LIU Fang, SUN Haopeng, YOU Qidong. Advances in small-molecule inhibitors targeting Hsp90-Cdc37 protein-protein interaction[J]. Journal of China Pharmaceutical University, 2015, 46(3): 272-278. DOI: 10.11665/j.issn.1000-5048.20150303

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Advances in small-molecule inhibitors targeting Hsp90-Cdc37 protein-protein interaction

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Abstract

Heat shock protein 90(Hsp90)which is a molecular chaperone that integrates multiple oncogenic pathways, is an important target in cancer therapy. The present research and development of the traditional N-terminal and C-terminal inhibitors has been restricted while targeting Hsp90 and cell division cycle protein Cdc37 has become the new direction of inhibiting Hsp90. Previous studies have demonstrated that various protein kinases rely on Cdc37 to load onto Hsp90 to complete their correct folding. Thus targeting Hsp90-Cdc37 is a promising strategy to inhibit protein kinases and alleviate the side effects. The interaction mechanism between Hsp90 and Cdc37 has become clearer in recent studies and many natural products have been reported to possess the ability to disassociate Hsp90-Cdc37. In this review, current knowledge on these small molecule inhibitors are summarized. The mode of action is also discussed as the references for the development of novel Hsp90 inhibitors.
- heat shock protein 90,
- cell division cycle protein 37,
- protein-protein interaction,
- advances

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[1]	Garcia-Carbonero R,Carnero A,Paz-Ares L.Inhibition of HSP90 molecular chaperones:moving into the clinic[J].Lancet Oncol,2013,14(9):358-369.
[2]	Rajan A, Kelly RJ, Trepel JB, et al. A phase I study of PF-04929113(SNX-5422),an orally bioavailable heat shock protein 90 inhibitor,in patients with refractory solid tumor malignancies and lymphomas[J].Clin Cancer Res,2011,17(21):6831-6839.
[3]	Jhaveri K, Taldone T, Modi S, et al. Advances in the clinical development of heat shock protein 90(Hsp90)inhibitors in cancers[J].Biochim Biophys Acta,2012,1823(3):742-755.
[4]	Joo JH,Dorsey FC,Joshi A,et al.Hsp90-Cdc37 chaperone complex regulates Ulk1-and Atg13-mediated mitophagy[J].Mol Cell,2011,43(4):572-585.
[5]	Ota A,Wang Y.Cdc37/Hsp90 protein-mediated regulation of IRE1alpha protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells[J].J Biol Chem,2012,287(9):6266-6274.
[6]	Erazo T, Moreno A, Ruiz-Babot G, et al. Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5(ERK5)nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex[J].Mol Cell Biol,2013,33(8):1671-1686.
[7]	Wang Y,Xu W,Zhou D,et al.Coordinated regulation of serum-and glucocorticoid-inducible kinase 3 by a C-terminal hydrophobic motif and Hsp90-Cdc37 chaperone complex[J].J Biol Chem,2014,289(8):4815-4826.
[8]	Sreeramulu S,Jonker HR,Langer T,et al.The human Cdc37.Hsp90 complex studied by heteronuclear NMR spectroscopy[J].J Biol Chem,2009,284(6):3885-3896.
[9]	Hieronymus H,Lamb J,Ross KN,et al.Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators[J].Cancer Cell,2006,10(4):321-330.
[10]	Zhang T,Hamza A,Cao X,et al.A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells[J].Mol Cancer Ther,2008,7(1):162-170.
[11]	Zhang T,Li Y,Yu Y,et al.Characterization of celastrol to inhibit Hsp90 and Cdc37 interaction[J].J Biol Chem,2009,284(51):35381-3539.
[12]	Sreeramulu S,Gande SL,Gobel M,et al.Molecular mechanism of inhibition of the human protein complex Hsp90-Cdc37,a kinome chaperone-cochaperone,by triterpene celastrol[J].Angew Chem Int Ed Engl,2009,48(32):5853-5855.
[13]	Yu Y,Hamza A,Zhang T,et al.Withaferin A targets heat shock protein 90 in pancreatic cancer cells[J].Biochem Pharmacol,2010,79(4):542-551.
[14]	Gu M,Yu Y,Gunaherath GM,et al.Structure-activity relationship(SAR)of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells[J].Invest New Drugs,2014,32(1):68-74.
[15]	Grover A,Shandilya A,Agrawal V,et al.Hsp90/Cdc37 chaperone/co-chaperone complex,a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A[J].BMC Bioinformatics, 2011,12(suppl 1):S30.
[16]	Wei H,Wei J,Hui-ling F,et al.Structure identification and anti-tumor activity research of FW-04-806[J].Chin J Antibiot(中国抗生素杂志),2011,7(36):874-877.
[17]	Huang W,Ye M,Zhang LR,et al.FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation[J].Mol Cancer,2014,13:150-163.
[18]	Clarke JD,Dashwood RH,Ho E.Multi-targeted prevention of cancer by sulforaphane[J].Cancer Lett,2008,269(2):291-304.
[19]	Rausch V,Liu L,Kallifatidis G,et al.Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics[J].Cancer Res,2010,70(12):5004-5013.
[20]	Lin LC,Yeh CT,Kuo CC,et al.Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/beta-catenin function[J].J Agric Food Chem,2012,60(28):7031-7039.
[21]	Gibbs A,Schwartzman J,Deng V,et al.Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6[J].Proc Natl Acad Sci U S A,2009,106(39):16663-16668.
[22]	Li Y,Karagoz GE,Seo YH,et al.Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37)complex and direct interactions with amino acids residues of Hsp90[J].J Nutr Biochem,2012,23(12):1617-1626.
[23]	Miyata Y. CK2: the kinase controlling the Hsp90 chaperone machinery[J].Cell Mol Life Sci,2009,66(11/12):1840-1849.
[24]	Dey B,Lightbody JJ,Boschelli F.CDC37 is required for p60v-src activity in yeast[J].Mol Biol Cell,1996,7(9):1405-1417.
[25]	Bandhakavi S,McCann RO,Hanna DE,et al.A positive feedback loop between protein kinase CKII and Cdc37 promotes the activity of multiple protein kinases[J].J Biol Chem,2003,278(5):2829-2836.
[26]	Abbas-Terki T,Donze O,Picard D.The molecular chaperone Cdc37 is required for Ste11 function and pheromone-induced cell cycle arrest[J].FEBS Lett,2000,467(1):111-116.
[27]	Lolli G,Cozza G,Mazzorana M,et al.Inhibition of protein kinase CK2 by flavonoids and tyrphostins.A structural insight[J].Biochemistry,2012,51(31):6097-6107.
[28]	Zhao M,Ma J,Zhu HY,et al.Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2,Cdc37 and Hsp90[J].Mol Cancer,2011,10(4):104-118.
[29]	He J,Niu X,Hu C,et al.Expression and purification of recombinant NRL-Hsp90alpha and Cdc37-CRL proteins for in vitro Hsp90/Cdc37 inhibitors screening[J].Protein Expr Purif,2013,92(1):119-127.

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