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Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09 Page 11 of 17

[123]
aminophosphonates were recently identified as weak or moderate inhibitors of cathepsin C , further
highlighting the potential of the phosphonate group as transition state analogs.

Moreover, two known epidermal growth factor receptor (EGFR) inhibitors containing Cys-reactive
acrylamide warheads were identified as cathepsin C inhibitors by activity-based protein profiling,
highlighting the potential of drug repurposing for the targeting of cathepsin C. In 2016, Canertinib, a former
drug candidate developed by Pfizer (USA) for the treatment of cancer, was identified as a potent
cathepsin C inhibitor with an IC value of 0.12 µM [Table 1]. Based on the structure of Canertinib, novel
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molecular probes with additional tags and/or click chemistry-compatible reactive groups were synthesized,
providing the potential basis for further development of selective cathepsin C inhibitors . Later, the same
[124]
group reported that the EGFR inhibitor WZ4002 inhibits cathepsin C with an IC value in the micromolar
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[125]
range . A new series of inhibitors developed on this scaffold led to the identification of a highly potent
and selective inhibitor, N-(5-((6-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)- 3-(piperidin-1-yl)
pyridin-2-yl)oxy)-2-methylphenyl)acrylamide (compound 22), [Table 1]. In vitro, the compound showed
concentration-dependent inhibition of cathepsin C activity in both THP1 and U937 cell-based assays, with
IC values of 2 and 3 nM, respectively. It also showed good metabolic stability and oral bioavailability and
50
resulted in efficient inhibition of downstream neutrophil serine peptidases in both bone marrow and blood
of mice .
[125]
Naturally occurring compounds are a rich source of pharmacologically active molecules and inhibition of
cathepsin C by such compounds has also been investigated to some extent. A recent study has shown that
polyglucoside from the vine Triperygium wilfordii inhibited cathepsin C activity in the serum, synovial fluid,
and tissues in a rat model of collagen-induced arthritis, highlighting the possibility that the suppression of
rheumatoid arthritis traditionally associated with Tripergyium wilfordii polyglucoside may be related to the
inhibition of cathepsin C and downstream serine peptidases . In addition, we found that caffeic acid and
[126]
its derivatives inhibit cysteine cathepsins, including cathepsin C [31,127] , in vitro. Since polyphenolic
compounds such as caffeic acid have a broad spectrum of pharmacological activity and biological targets,
their use for specific targeting of individual protein targets is not feasible. Nevertheless, caffeic acid is
considered a promising pharmacophore for the development of specific inhibitors . Alternative methods
[128]
for targeting cathepsin C are also emerging. We have identified 3’-nitrophthalanilic acid as a partial
inhibitor of cathepsins K and C that presumably acts by binding outside of the active site [31,129] . Such
allosteric drugs are a popular and promising approach for the targeting of membrane receptors and
[130]
strategies of targeting sites away from the active site have also been explored in several PLPs, including
human cathepsin K [131,132] and plasmodial cathepsin C homologs . However, in the case of human
[133]
cathepsin C, the development of specific partial inhibitors suitable for use in cell culture and in vivo and the
evaluation of the efficacy of such an approach are still in their infancy.

CONCLUSION
Although cathepsin C was among the first peptidases to be identified, interest in this peptidase as a drug
target has only emerged in the last two decades, primarily leading to facilitated investigation of its
physiological and pathological roles. With two inhibitors currently in clinical trials for the treatment of non-
cystic fibrosis bronchiectasis, cathepsin C is currently the most important and promising human cysteine
cathepsin from a clinical perspective. Considering the recent failures in the field of peptidase targeting, e.g.,
the cathepsin K inhibitor odanacatib (Merck & Co., USA) for the treatment of osteoporosis which was
[134]
discontinued after the completion of phase 3 clinical trials , the outcomes of these trials may be crucial to
(re)establish not only cathepsin C, but cysteine cathepsins and peptidases in general as valid drug targets in
human diseases. From the perspective of basic protein science, cathepsin C is proving to be an interesting