Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools
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Sylvie Desmarais
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 IC50 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 [14C]-balicatib in fibroblasts is blocked by prior treatment of the cells with NH4Cl, 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.
©2009 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Review
- Dimeric/oligomeric DNA methyltransferases: an unfinished story
- Minireview
- Induced human pluripotent stem cells: promises and open questions
- Genes and Nucleic Acids
- Effect of a quaternary pentamine on RNA stabilization and enzymatic methylation
- Protein Structure and Function
- A soluble form of ammonia monooxygenase in Nitrosomonas europaea
- Metzincin's canonical methionine is responsible for the structural integrity of the zinc-binding site
- A dual role of the N-terminal FQQI motif in GLUT4 trafficking
- Molecular Medicine
- Peritumoral administration of GPI-anchored TIMP-1 inhibits colon carcinoma growth in Rag-2 γ chain-deficient mice
- Cell Biology and Signaling
- The effect of endogenous preproneuropeptide Y leucine 7 to proline 7 polymorphism on growth and apoptosis in primary cultured HUVECs
- Cross talk between kinin and angiotensin II receptors in mouse abdominal aorta
- Advanced glycation end product accumulation in rho0 cells without a functional respiratory chain
- Proteolysis
- Association between kallikrein-related peptidases (KLKs) and macroscopic indicators of semen analysis: their relation to sperm motility
- Catalytic properties of recombinant dipeptidyl carboxypeptidase from Escherichia coli: a comparative study with angiotensin I-converting enzyme
- Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools
