A synthetic bis-dichloroacetate ester of the natural product honokiol, is an allosteric inhibitor of the mitochondrial chaperone TRAP1.1 It binds to an allosteric site on TRAP1 leading to inhibition (IC50 ~8mM) and is selective over HSP90, unlike 17-AAG and radicicol which are nonselective. Inhibition of TRAP1 leads to upregulation of succinate dehydrogenase and the mitochondrial deacetylase SIRT3. In neoplastic cells HDCA decreases proliferation, increases mitochondrial superoxide levels and abolishes tumorigenic growth.1 HDCA demonstrated in vivo activity against vemurafenib-resistant (LM36R) melanoma.2
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