title: Potent and selective cathepsin L inhibitors do not inhibit human osteoclast resorption in vitro.
abstract: Cathepsins K and L are related cysteine proteases that have been proposed to play important roles in osteoclast-mediated bone resorption. To further examine the putative role of cathepsin L in bone resorption, we have evaluated selective and potent inhibitors of human cathepsin L and cathepsin K in an in vitro assay of human osteoclastic resorption and an in situ assay of osteoclast cathepsin activity. The potent selective cathepsin L inhibitors (K(i) = 0.0099, 0.034, and 0.27 nm) were inactive in both the in situ cytochemical assay (IC(50) > 1 micrometer) and the osteoclast-mediated bone resorption assay (IC(50) > 300 nm). Conversely, the cathepsin K selective inhibitor was potently active in both the cytochemical (IC(50) = 63 nm) and resorption (IC(50) = 71 nm) assays. A recently reported dipeptide aldehyde with activity against cathepsins L (K(i) = 0.052 nm) and K (K(i) = 1.57 nm) was also active in both assays (IC(50) = 110 and 115 nm, respectively) These data confirm that cathepsin K and not cathepsin L is the major protease responsible for human osteoclastic bone resorption.
authors.affiliation: Departments of Bone and Cartilage Biology, Medicinal Chemistry, Protein Biochemistry, and Mechanistic Enzymology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. ian_e_james@sbphrd.com
authors.forename: I E
authors.initials: IE
authors.lastname: James
authors.forename: R W
authors.initials: RW
authors.lastname: Marquis
authors.forename: S M
authors.initials: SM
authors.lastname: Blake
authors.forename: S M
authors.initials: SM
authors.lastname: Hwang
authors.forename: C J
authors.initials: CJ
authors.lastname: Gress
authors.forename: Y
authors.initials: Y
authors.lastname: Ru
authors.forename: D
authors.initials: D
authors.lastname: Zembryki
authors.forename: D S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: M S
authors.initials: MS
authors.lastname: McQueney
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: H J
authors.initials: HJ
authors.lastname: Oh
authors.forename: M
authors.initials: M
authors.lastname: Gowen
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
authors.forename: M W
authors.initials: MW
authors.lastname: Lark
mesh_terms: D001862:Bone Resorption; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D010450:Endopeptidases; D006801:Humans; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L