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Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools.
- Source :
-
Biological chemistry [Biol Chem] 2009 Sep; Vol. 390 (9), pp. 941-8. - Publication Year :
- 2009
-
Abstract
- Cathepsin K (Cat K) degrades bone type I collagen and is a target for the pharmacological treatment of osteoporosis. Further roles for Cat K have been recently described, some of which are supported by the use of purportedly selective Cat K inhibitors in human and rodent cell-based assays. Twelve commercial and non-commercial Cat K inhibitors were profiled against a panel of purified human, rat, and mouse cysteine cathepsins and in two cell-based enzyme occupancy assays for activity against Cat K, B, and L. Ten inhibitors, including the carbohydrazide Cat K inhibitor II (Boc-Phe-Leu-NHNH-CO-NHNH-Leu-Z), the non-covalent K4b, and the epoxide NC-2300, have either little Cat K selectivity, or appear poorly cell penetrant. The amino-acetonitrile-containing inhibitors L-873724 and odanacatib show greater than 100-fold human Cat K enzyme selectivity and have similar IC(50) values against each cathepsin in cell-based and enzyme assays. The basic inhibitor balicatib has greater cellular potencies than expected on the basis of purified enzyme assays. The accumulation of [(14)C]-balicatib in fibroblasts is blocked by prior treatment of the cells with NH(4)Cl, consistent with balicatib having lysosomotropic properties. These results support the use of L-873724 and odanacatib as tools to identify novel roles for Cat K using human cell-based systems, but suggest using caution in the interpretation of studies employing the other compounds.
- Subjects :
- Animals
Benzamides pharmacology
Biphenyl Compounds pharmacology
Cathepsin K
Cell Line
Cell Line, Tumor
Epoxy Compounds pharmacology
Humans
Hydrazines pharmacology
Mice
Molecular Structure
Piperazines pharmacology
Rabbits
Rats
Cathepsins antagonists & inhibitors
Fibroblasts drug effects
Protease Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1437-4315
- Volume :
- 390
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19453281
- Full Text :
- https://doi.org/10.1515/BC.2009.092