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J. Biol. Chem., Vol. 279, Issue 49, 51131-51140, December 3, 2004

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Small Molecule Modulators of Endogenous and Co-chaperone-stimulated Hsp70 ATPase Activity^*

Sheara W. Fewell, Christine M. Smith, Michael A. Lyon¶, Teodora Pene Dumitrescu||, Peter Wipf¶, Billy W. Day¶||, and Jeffrey L. Brodsky**

From the Departments of Biological Sciences, ^¶Chemistry, and ^||Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

The molecular chaperone and cytoprotective activities of the Hsp70 and Hsp40 chaperones represent therapeutic targets for human diseases such as cancer and those that arise from defects in protein folding; however, very few Hsp70 and no Hsp40 modulators have been described. Using an assay for ATP hydrolysis, we identified and screened small molecules with structural similarity to 15-deoxyspergualin and NSC 630668-R/1 for their effects on endogenous and Hsp40-stimulated Hsp70 ATPase activity. Several of these compounds modulated Hsp70 ATPase activity, consistent with the action of NSC 630668-R/1 observed previously (Fewell, S. W., Day, B. W., and Brodsky, J. L. (2001) J. Biol. Chem. 276, 910–914). In contrast, three compounds inhibited the ability of Hsp40 to stimulate Hsp70 ATPase activity but did not affect the endogenous activity of Hsp70. Two of these agents also compromised the Hsp70/Hsp40-mediated post-translational translocation of a secreted pre-protein in vitro. Together, these data indicate the potential for continued screening of small molecule Hsp70 effectors and that specific modulators of Hsp70-Hsp40 interaction can be obtained, potentially for future therapeutic use.

Received for publication, April 30, 2004 , and in revised form, September 8, 2004.

^* This work was supported in part by National Institutes of Health Grants CA78039 (to P. W. and B. W. D.), CA099024 (to J. L. B.), and GM067082 (to the University of Pittsburgh Center for Chemical Methodologies and Library Development). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a National Institutes of Health National Research Service Award.

^** To whom correspondence should be addressed: Dept. of Biological Sciences, 274 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260. Tel.: 412-624-4831; Fax: 412-624-4759; E-mail: jbrodsky{at}pitt.edu.

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