DNA-catalyzed hydrolysis of esters and aromatic amides

Relief of procaspase inhibition enhances the potency of cancer chemotherapeutics Botham RC, Fan TM, Hergenrother PJ Manipulation of the apoptotic cascade is an effective and commonly employed strategy for the eradication of cancer cells. This work utilizes the small molecule PAC-1 to target the labile zinc pool, a physiological inhibitor of apoptosis. Labile zinc inhibits the conversion of procaspase-3 to caspase-3, preventing the activation of this key executioner of apoptosis. Aiming to harness the potential of active caspases for the treatment of cancer, we developed PAC-1, a mild zinc chelator (Kd ~ 42 nM) to facilitate caspase activation. PAC-1 rapidly enters cells and reduces the level of labile zinc, inducing apoptotic cell death, and has shown efficacy in multiple animal models of cancer. Recently we have used treatment with PAC-1 to prime cells for more effective treatment by cancer chemotherapeutics. By relieving the zinc-mediated inhibition of the procaspases, cancer cells are more responsive to cell death signals. This increase in potency, driven by primed and uninhibited procaspase-3, has been shown in cell culture, demonstrated mechanistically, and validated in animal models of cancer. Thus, PAC-1, a well-tolerated compound with significant single agent anticancer activity, has the capacity to increase the efficacy of a diverse panel of chemotherapeutics. Labile zinc chelation may therefore serve as a general strategy to increase the apoptotic potential of the cell and be a general strategy for potentiation in vivo. 2