HSP40: Inhibitors

Only a few studies have been devoted to develop inhibitors of DnaJ/Hsp40. Drugs that are correlated with an overrexpression of DnaJ/Hsp40 comprise andrographolide from Andrographis paniculata [Burm. f.] Nees, curcumin, geldanamycin, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-AAG), radicicol (bortezomib, velcade), celastrol, 5-fluorouracil (5-FU) or carboplatin. In contrast, compounds that have been correlated with downregulated levels of DnaJ/Hsp40 include the benzylidene lactam compound, KNK437 (N-formyl-3,4-methylenedioxy-benzylidene-γbutyrolactam) and the bioflavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavon); see Drug Discovery for more detailed information. Apart from its inhibitory action of HSP expression, quercetin (Figure 6) has also been reported to inhibit the acquisition of thermotolerance in human colon carcinoma cells ⁴¹³. KNK437 (Figure 6) dose-dependently inhibits the acquisition of thermotolerance and the induction of various HSPs including Hsp40, Hsp70, and Hsp105 in human colon carcinoma cells ⁴¹⁴. Although this compound inhibited the acquisition of thermotolerance, it did not increase thermosensitivity in non-tolerant cells. Compared to quercetin, the inhibitory effect of KNK437 is much more pronounced ⁴¹⁴. A more recent study indicated that quercetin promotes dimerization of the neuroprotective DNAJ/HSP40 DnaJC5/Csp-α via the unique cysteine string region ⁴¹⁵. Additionally, quercetin-induced DnaJC5/Csp-α dimerization correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with DnaJC5/Csp-α function in primary cultures of Lymnaea neurons ⁴¹⁵.

A novel class of small molecule inhibitors has currently been described to bind directly to DnaJ/Hsp40 comprising derivatives of phenoxy-N-arylacetamide. Amongst them, butyl 3-[2-(2,4-dichlorophenoxy)acetamido]benzoate (Figure 6) binds to DnaJ and inhibits Hsp70/DnaJ protein refolding with an IC₅₀ value of 0.13 μM ⁴¹⁶. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These findings highlight the therapeutic and diagnostic potential of DnaJ/Hsp40 in numerous pathological and non-pathological conditions.