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J Am Chem Soc. 2014 Jan 29;136(4):1312-9. doi: 10.1021/ja4124303. Epub 2014 Jan 16.

Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity.

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  • 1Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.


Combination anticancer therapy typically consists of drugs that target different biochemical pathways or those that act on different targets in the same pathway. Here we demonstrate a new concept in combination therapy, that of enzyme activation with two compounds that hit the same biological target, but through different mechanisms. Combinations of procaspase-3 activators PAC-1 and 1541B show considerable synergy in activating procaspase-3 in vitro, stimulate rapid and dramatic maturation of procaspase-3 in multiple cancer cell lines, and powerfully induce caspase-dependent apoptotic death to a degree well exceeding the additive effect. In addition, the combination of PAC-1 and 1541B effectively reduces tumor burden in a murine lymphoma model at dosages for which the compounds alone have minimal or no effect. These data suggest the potential of PAC-1/1541B combinations for the treatment of cancer and, more broadly, demonstrate that differentially acting enzyme activators can potently synergize to give a significantly heightened biological effect.

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