title: Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place, Waco, TX 76798, USA.
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Chavarria
authors.forename: Michael R
authors.initials: MR
authors.lastname: Horsman
authors.forename: Wara M
authors.initials: WM
authors.lastname: Arispe
authors.forename: G D Kishore
authors.initials: GD
authors.lastname: Kumar
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Erica N
authors.initials: EN
authors.lastname: Parker
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; C581086:KGP94; D013882:Thiosemicarbazones; D056668:Cathepsin L; D013890:Thiourea