HSP90 molecular chaperone

In their approach towards novel antitumor agents, Danishefsky and coworkers [22] recently published another interesting example of a domino Diels-Alder/retro-Diels-Alder reaction. These authors were attracted by the 14-membered resor-cinylic macrolide radicol (4-67) which inhibits the Hsp90 molecular chaperone [23,... 

Roe, S.M., Prodromou, C., O Brien, R., Ladbury, J.E., Piper, P.W. and Pearl, L.H. (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin. Journal of Medicinal Chemistry, 42, 260-266. 

Roe SM, Prodromou C, O Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin. J Med Chem 42 260... 

Pearl LH, Prodromou C. Structure and mechanism of the hsp90 molecular chaperone machinery. Annu. Rev. Biochem. 2006 75 271-294. 

VER-49009 <2005JME4212> have been reported. The crystal structure of human Hsp90a complexed with dihy-droxyphenylpyrazoles has also been reported <2005BML1475>. Similarly, 3-(5-chloro-2,4-dihydroxyphenyl)pyra-zole-4-carboxamides were also studied as inhibitors of Hsp90 molecular chaperone <2005BML5197>. 

Brough PA, Barril X, Borgognoni J et al (2009) Combining hit identification strategies fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52 4794—4809... 

Brough PA et al (2005) 3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone. Bioorg Med Chem Lett 15(23) 5197-5201... 

STRUCTURE, FUNCTION, AND MECHANISM OF THE Hsp90 MOLECULAR CHAPERONE... 

P., et al (2011) Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone. Bioorganic and Medicinal Chemistry Letters, 21, 3557-3562. 

Synthesis of pyrazole-type inhibitors of Hsp90 molecular chaperone... 

Hsp90 is a molecular chaperon required for the refolding of proteins in cells exposed to environmental stress. It contains an ATP-binding pocket in its amino terminus. Several natural products, for example radicicol (230) (Scheme 48), bind to this pocket and inhibit its chaperon function, which is mirrored in enhanced proteosomal degradation of Hsp90 client proteins, so that compounds like 230 are of interest as novel anticancer agents. 

Imai, j., Maruya, M., Yashiroda, H., Yahara, 1., and Tanaka, K. The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome. Embo J 2003, 22, 3557-67. 

The complexity of regulation of Raf kinase was shown by the discovery of a further three proteins which can specifically associate with Raf kinase (review Morrison and Cutler, 1997, Sternberg and Alberola-Ila, 1998). Members of the family of 14-3-3 proteins are found associated with Raf kinase. The 14-3-3 proteins recognize and bind phosphoserine residues in a particular sequence environment. It is assumed that the 14-3-3 proteins bind to Ser-phosphate residues of Raf kinase and thereby fix it in an inactive conformation. Other Raf-interacting proteins include the molecular chaperones hsp90 and p50. These proteins appear to be important for maintaining protein stability and for the proper localization of Raf kinase within the cell. 

Sequence Comparisons Proteins called molecular chaperones (described in Chapter 4) assist in the process of protein folding. One class of chaperone found in organisms from bacteria to mammals is heat shock protein 90 (Hsp90). All Hsp90 chaperones contain a 10 amino acid signature sequence, which allows for ready identification of these proteins in sequence databases. Two representations of this signature sequence are shown below. 

Kim, J. et al. 2004. Development of a fluorescence polarization assay for the molecular chaperone Hsp90../. Biomol. Screen. 9, 375-381. 

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