Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.
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| Abstract |
The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.
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| Authors | Jean-Pierre Falgueyret, Sylvie Desmarais, Renata Oballa, W Cameron Black, Wanda Cromlish, Karine Khougaz, Sonia Lamontagne, Frederic Massé, Denis Riendeau, Sylvie Toulmond, M David Percival |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 24 Pg. 7535-43 (Dec 01 2005) ISSN: 0022-2623 [Print] United States |
| PMID | 16302795 (Publication Type: Journal Article) |
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