%0 Journal Article
%@ 0021-9258
%A Fewell, SW
%A Smith, CM
%A Lyon, MA
%A Dumitrescu, TP
%A Wipf, P
%A Day, BW
%A Brodsky, JL
%D 2004
%F pittir:20393
%J Journal of Biological Chemistry
%N 49
%P 51131 - 51140
%T Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity
%U http://d-scholarship-dev.library.pitt.edu/20393/
%V 279
%X 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.