kgp94 and Disease-Models--Animal

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.

Topics: Animals; Antineoplastic Agents; Cathepsin L; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cysteine Proteinase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Human Umbilical Vein Endothelial Cells; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Thiosemicarbazones; Thiourea