Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L

Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a transient covalent bond, and are supported by molecular modeling that places the thiocarbonyl of the inhibitor in proximity to the thiolate moiety of the enzyme active site Cys25. KGP94 significantly decreased the activity of cathepsin L toward human type I collagen, and impeded both migration and invasion of MDA-MB-231 human breast cancer cells. Growth retardation was achieved in vivo against both recently implanted and established tumours using a C3H mouse mammary carcinoma model.

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► KGP94 is a reversible, time-dependent and competitive inhibitor of human cathepsin L.
► KGP94 inhibits the activity of cathepsin L toward human type I collagen.
► KGP94 significantly impedes both migration and invasion of MDA-MB-231 human breast cancer cells.
► Molecular modeling places the thiocarbonyl of KGP94 in proximity to the active site Cys25.
► Significant growth retardation of C3H mouse mammary carcinomas is achieved with KGP94 treatment.