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Published on: February 23, 2024
Identification and characterization of the novel reversible and selective cathepsin X inhibitors
Urša Pečar Fonović1, Ana Mitrović2, Damijan Knez2
1Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, Slovenia. ursa.pecarfonovic@ffa.uni-lj.si.
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.
Insights
Researchers identified novel triazole-based inhibitors targeting cathepsin X, an enzyme implicated in cancer and neurodegenerative diseases. Compound 22 shows potent and selective inhibition, offering therapeutic potential without cytotoxicity.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Cathepsin X, a cysteine peptidase, plays a role in cancer and neurodegenerative disease progression.
- Targeting cathepsin X with selective inhibitors presents a promising therapeutic strategy.
Purpose of the Study:
- To identify and characterize novel, selective, and reversible inhibitors of cathepsin X.
- To evaluate the therapeutic potential of these inhibitors in cellular models.
Main Methods:
- Synthesis and screening of triazole-based compounds as cathepsin X inhibitors.
- Assessment of inhibitor selectivity against related cysteine peptidases.
- Evaluation of compound cytotoxicity and functional effects on cancer and neuronal cells.
Main Results:
- Triazole-benzodioxine derivatives were identified as potent and selective cathepsin X inhibitors.
- Compound 22 demonstrated the highest potency (Ki = 2.45 ± 0.05 μM) and >100-fold selectivity over cathepsin B.
- Compound 22 exhibited no cytotoxicity to PC-3 or PC-12 cells and effectively inhibited tumor cell migration while promoting neurite outgrowth.
Conclusions:
- Compound 22 is a highly potent and selective cathepsin X inhibitor with significant therapeutic potential.
- The identified inhibitors warrant further investigation for in vivo applications in cancer and neurodegenerative diseases.
