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 microM) with at least 100-fold greater selectivity in comparison to cathepsin B or other related cysteine peptidases.
COBISS.SI-ID: 4382065
Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against cathepsin X compared to Z9, with IC50 values of 7.1 micorM-13.6 microM. Additionally, 25 inhibited prostate cancer cell migration by 21%, which is under the control of cathepsin X.
COBISS.SI-ID: 4896113
We have investigated the contribution of both cathepsins B and X in epithelial/mesenchymal transition (EMT) using tumor cell lines differing in their expression of epithelial and mesenchymal markers and cell morphology. Higher levels of both cathepsins are shown to promote EMT and are associated with the mesenchymal-like cell phenotype. Moreover, simultaneous knockdown of the two peptidases triggers a reverse, mesenchymal to epithelial transition. Of the two cathepsins, cathepsin B appears to be the stronger promotor of EMT. Furthermore, we evaluated the involvement of cathepsin B and X in the transforming growth factor-beta1 (TGF-beta1) signaling pathway, one of the key signaling mechanisms triggering EMT in cancer. In MCF-7 cells the expression of cathepsin B was shown to depend on their activation with TGF-beta1 while, for cathepsin X, a TGF-beta1 independent mechanism of induction during EMT is indicated.
COBISS.SI-ID: 4323185
In the review paper we provided extensive information on the role of lysosomal peptidases, in particular cysteine cathepsins in innate immunity. We exposed their role in regulation of antigen presentation, Toll-like receptor signaling, cytokine secretion, apoptosis, autophagy, differentiation, migration and cytotoxicity.
COBISS.SI-ID: 4859761
Increased proteolytic activity of cysteine cathepsins has long been known to facilitate malignant progression, and it has also been associated with tumor-promoting roles of myeloid-derived suppressor cells (MDSCs). Here, we demonstrate the potential of the MDA-MB-231 breast cancer cell line to generate functional MDSCs from CD14+ cells of healthy human donors. During this transition to MDSCs, the overall levels of cysteine cathepsins increased, with the largest responses for cathepsins L and X. Interactions with peripheral blood mononuclear cells reduced MDA-MB-231 cell invasion, while inhibition of cathepsin X activity by Z9 restored invasion. Inhibition of cathepsin L activity significantly increased CD8+ cytotoxicity. Together, our findings underlie the importance of tumor cell-immune cell interactions in the evaluation of the anti-cancer potential of cysteine cathepsin inhibitors.
COBISS.SI-ID: 14118403