Abstract
Cathepsin X is a cysteine peptidase involved in the progression of cancer and neurodegenerative diseases. Targeting this enzyme with selective inhibitors opens a new possibility for intervention in several therapeutic areas. In this study triazole-based reversible and selective inhibitors of cathepsin X have been identified. Their selectivity and binding is enhanced when the 2,3-dihydrobenzo[b][1,4]dioxine moiety is present as the R1 substituent. Of a series of selected triazole-benzodioxine derivatives, compound 22 is the most potent inhibitor of cathepsin X carboxypeptidase activity (Ki = 2.45 ± 0.05 μM) with at least 100-fold greater selectivity in comparison to cathepsin B or other related cysteine peptidases. Compound 22 is not cytotoxic to prostate cancer cells PC-3 or pheochromocytoma PC-12 cells at concentrations up to 10 μM. It significantly inhibits the migration of tumor cells and increases the outgrowth of neurites, both processes being under the control of cathepsin X carboxypeptidase activity. Compound 22 and other characterized triazole-based inhibitors thus possess a great potential for further development resulting in several in vivo applications.
Highlights
Cathepsin X is a carboxypeptidase expressed predominantly in immune and neuronal cells[1]
There is increasing evidence showing that cathepsin X is involved in a variety of pathological processes leading to neurodegeneration, progression of cancer and other diseases
Excessive proteolytic activity cannot be balanced by endogenous inhibitors, and the number of exogenous inhibitors that could be used as potential drugs is small
Summary
Cathepsin X is a carboxypeptidase expressed predominantly in immune and neuronal cells[1]. NPrNH-(2 S,3 S)tEps-Ile-OH, designed to place a single amino acid residue in the S’ subsite of cathepsin X, has a 10-fold preference over cathepsins B or L, it still exhibits a relatively weak inhibitory potency toward cathepsin X (kinact/Ki = 225 M–1s–1)[13] Another epoxysuccinyl-based inhibitor of cathepsin X is AMS36 which has a naphthalene methylamine in P3 and a non-natural p-methyl phenylalanine moiety in the P2 position[14]. Triazole-based reversible cathepsin X inhibitors, resulting from an in-house compound library screening, are described They exhibit values of Ki in the low micromolar range, high selectivity for cathepsin X, and are not cytotoxic for PC-3 prostate cancer cells or PC-12 pheochromocytoma cells. The inhibitors were further evaluated in cell based assays where their impact on tumor cell migration and neurite outgrowth, two processes strongly associated with increased cathepsin X activity, was established
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