Brain-permeable small-molecule inhibitors of Hsp90 prevent α-synuclein oligomer formation and rescue α-synuclein-induced toxicity

Journal of Pharmacology and Experimental Therapeutics

Volumn 332, Issue 3, 2010, Pages 849-857

  Putcha, Preeti ^a   Danzer, Karin M ^a   Kranich, Lisa R ^a   Scott, Anisa ^b   Silinski, Melanie ^b   Mabbett, Sarah ^b   Hicks, Carol D ^c   Veal, James M ^b   Steed, Paul M ^b   Hyman, Bradley T ^a   McLean, Pamela J ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b Serenex Inc   (United States)

^c PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(2 FLUORO 6 [TETRAHYDROFURAN 3 YLAMINO] 4 (3,6,6 TRIMETHYL 4 OXO 4,5,6,7 TETRAHYDRO 1H INDOL 1 YL)BENZAMIDE); 4 [6,6 DIMETHYL 4 OXO 3 (TRIFLUOROMETHYL) 4,5,6,7 TETRAHYDRO 1H INDAZOL 1 YL] 2 [(TRANS 4 HYDROXYCYCLOHEXYL)AMINO]BENZAMIDE; ALPHA SYNUCLEIN; GELDANAMYCIN; HEAT SHOCK PROTEIN 70; HEAT SHOCK PROTEIN 90 INHIBITOR; SNX 0723; SNX 2112; SNX 3113; SNX 3723; SNX 8891; TANESPIMYCIN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN; CANCER CELL CULTURE; CONCENTRATION (PARAMETERS); CYTOTOXICITY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG STRUCTURE; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; HUMAN CELL; IN VIVO STUDY; MEMBRANE PERMEABILITY; NEUROPROTECTION; NONHUMAN; OLIGOMERIZATION; PARKINSON DISEASE; PLASMID; PRIORITY JOURNAL; PROTEIN DETERMINATION; PROTEIN EXPRESSION; RAT; SPRAGUE DAWLEY RAT;

ADMINISTRATION, ORAL; ALPHA-SYNUCLEIN; ANIMALS; ANTHRANILIC ACIDS; BIOLOGICAL AVAILABILITY; BRAIN; CELL MEMBRANE PERMEABILITY; FEMALE; HSP90 HEAT-SHOCK PROTEINS; HUMANS; INDOLES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSFECTION;

EID: 77249101456     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.109.158436     Document Type: Article

References (40)

1. Ansar S, Burlison JA, Hadden MK, Yu XM, Desino KE, Bean J, Neckers L, Audus KL, Michaelis ML, and Blagg BS (2007) A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity. Bioorg Med Chem Lett 17:1984-1990.
2. Auluck PK, Meulener MC, and Bonini NM (2005) Mechanisms of Suppression of {alpha}-Synuclein neurotoxicity by geldanamycin in Drosophila. J Biol Chem 280: 2873-2878.
3. Barta TE, Veal JM, Rice JW, Partridge JM, Fadden RP, Ma W, Jenks M, Geng L, Hanson GJ, Huang KH, et al. (2008) Discovery of benzamide tetrahydro-4Hcarbazol-4-ones as novel small molecule inhibitors of Hsp90. Bioorg Med Chem Lett 18:3517-3521.
4. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, Fadden P, Partdrige J, Hall S, Steed P, et al. (2008) SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 14:240-248.
5. Chiosis G and Tao H (2006) Purine-scaffold Hsp90 inhibitors. IDrugs 9:778-782.
6. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, and Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrilization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci U S A 97:571-576.
7. Cysyk RL, Parker RJ, Barchi JJ Jr, Steeg PS, Hartman NR, and Strong JM (2006) Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications. Chem Res Toxicol 19:376-381.
8. Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B, and Kostka M (2007) Different species of {alpha}-synuclein oligomers induce calcium influx and seeding. J Neurosci 27:9220-9232.
9. Dedmon MM, Christodoulou J, Wilson MR, and Dobson CM (2005) Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 280:14733-14740.
10. Dickey CA, Eriksen J, Kamal A, Burrows F, Kasibhatla S, Eckman CB, Hutton M, and Petrucelli L (2005) Development of a high throughput drug screening assay for the detection of changes in tau levels-proof of concept with HSP90 inhibitors. Curr Alzheimer Res 2:231-238.
11. El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, and Allsop D (2006) Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 20:419-425.
12. Fujikake N, Nagai Y, Popiel HA, Okamoto Y, Yamaguchi M, and Toda T (2008) Heat shock transcription factor 1-activating compounds suppress polyglutamineinduced neurodegeneration through induction of multiple molecular chaperones. J Biol Chem 283:26188-26197.
13. Heath EI, Gaskins M, Pitot HC, Pili R, Tan W, Marschke R, Liu G, Hillman D, Sarkar F, Sheng S, et al. (2005) A phase II trial of 17-allylamino-17- demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Prostate Cancer 4:138-141.
14. Jankovic J and Stacy M (2007) Medical management of levodopa-associated motor complications in patients with Parkinson's disease. CNS Drugs 21:677-692.
15. Klucken J, Shin Y, Masliah E, Hyman BT, and McLean PJ (2004) Hsp70 Reduces alpha-Synuclein aggregation and toxicity. J Biol Chem 279:25497-25502.
16. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, and Riess O (1998) Ala30Pro mutation in the gene encoding a-synuclein in Parkinson's disease. Nat Genet 18:106-108.
17. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, and Hyman BT (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem 83:846-854.
18. McLean PJ, Klucken J, Shin Y, and Hyman BT (2004) Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321:665-669.
19. Moller JC, Eggert KM, Unger M, Odin P, Chaudhuri KR, and Oertel WH (2008) Clinical risk-benefit assessment of dopamine agonists. Eur J Neurol 15 (Suppl 2):15-23.
20. Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, Rice J, Barabasz A, Foley B, Ikeda H, et al. (2009) SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood 113:846-855.
21. Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, and McLean PJ (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS ONE 3:e1867.
22. Ouyang YB, Xu L, and Giffard RG (2005) Geldanamycin treatment reduces delayed CA1 damage in mouse hippocampal organotypic cultures subjected to oxygen glucose deprivation. Neurosci Lett 380:229-233.
23. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, et al. (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703-714.
24. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, et al. (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276:2045-2047.
25. Ramanathan RK, Trump DL, Eiseman JL, Belani CP, Agarwala SS, Zuhowski EG, Lan J, Potter DM, Ivy SP, Ramalingam S, et al. (2005) Phase I pharmacokineticpharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11:3385-3391.
26. Remy I and Michnick SW (2006) A highly sensitive protein-protein interaction assay based on Gaussia luciferase. Nat Methods 3:977-979.
27. Rice JW, Veal JM, Fadden RP, Barabasz AF, Partridge JM, Barta TE, Dubois LG, Huang KH, Mabbett SR, Silinski MA, et al. (2008) Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum 58:3765-3775.
28. Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, et al. (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3:498-507.
29. Schulte TW and Neckers LM (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42:273-279.
30. Shin Y, Klucken J, Patterson C, Hyman BT, and McLean PJ (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727-23734.
31. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, et al. (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302:841.
32. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, and Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839-840.
33. Taldone T, Gozman A, Maharaj R, and Chiosis G (2008) Targeting Hsp90: smallmolecule inhibitors and their clinical development. Curr Opin Pharmacol 8:370-374.
34. Tannous BA, Kim DE, Fernandez JL, Weissleder R, and Breakefield XO (2005) Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol Ther 11:435-443.
35. Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, and McLean PJ (2008) CHIP targets toxic alpha-synuclein oligomers for degradation. J Biol Chem 283:17962-17968.
36. Uversky VN, Li J, and Fink AL (2001) Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 276:10737-10744.
37. Volles MJ and Lansbury PT Jr (2003) Zeroing in on the pathogenic form of alphasynuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42:7871-7878.
38. Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, and Sobue G (2006) Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG). Ann N Y Acad Sci 1086:21-34.
39. Xiao N, Callaway CW, Lipinski CA, Hicks SD, and DeFranco DB (1999) Geldanamycin provides posttreatment protection against glutamate-induced oxidative toxicity in a mouse hippocampal cell line. J Neurochem 72:95-101.
40. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164-173.