Page 74 - Read Online

Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09 Page 9 of 17

Figure 2. Reversible nitrile warhead-containing inhibitors of cathepsin C. (A) Chemical structure of compounds AZD5258 developed by
AstraZeneca; (B) Crystal structure of AZDB5248 bound into the active site of cathepsin C. (PDB accession code 4CDE); (C) Chemical
structure of the IcatC XPZ-01 analog used for crystallization; (D) Crystal structure of IcatC XPZ-01 analog bound into the active site of
cathepsin C (PDB accession code 6IC6). Chemical structures were drawn with ChemDraw software. The crystal structures in panels B
and D were drawn with UCSF Chimera software [113] .

[104]
AZD7986 was the first nitrile-based cathepsin C inhibitor to reach clinical trials . In 2016, Insmed, Inc
(USA) announced a license agreement with AstraZeneca for exclusive worldwide rights to AZD7986. The
compound was renamed INS1007 (trade name brensocatib) and was used in a trial study for the treatment
of non-cystic fibrosis bronchiectasis, a persistent dilatation of the airways associated with neutrophil-
mediated inflammation . In the 24-week phase 2 study, which ended in 2020, patients treated with
[76]
[105]
brensocatib showed reduced NSP activity, which was associated with the clinical effect of bronchiectasis .
These results confirmed the efficacy of brensocatib in the treatment of chronic neutrophil-related
inflammatory diseases in the lung. A phase 3 clinical trial is currently underway . Neutrophils and their
[7]
peptidases are also associated with the severity of COVID-19 [106,107] . Therefore, brensocatib has also been
evaluated for its beneficial effects in hospitalized patients with COVID-19. Unfortunately, brensocatib did
not improve the clinical condition of COVID-19 patients .
[108]

Another promising nitrile-based inhibitor of cathepsin C is the compound IcatC XPZ-01 ((S)-2-amino-N-
((1R,2R)-1-cyano-2-(4’-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide) [Table 1].
IcatC XPZ-01 is a reversible, potent, and cell-permeable inhibitor with an IC value of 15 ± 1 nM and excellent
50
selectivity for cathepsin C . The crystal structure of one of its derivatives bound to the active site of
[78]
cathepsin C revealed a binding pose analogous to that of AZD5248 [Figure 2] . The compound
[109]
successfully inhibited the activation of NSPs in bone marrow in both cell-based assays and primate
experiments . In mice, sufficient concentrations of IcatC XPZ-01 were accumulated in the bone marrow to
[78]
inhibit cathepsin C, and subcutaneous administration of the inhibitor showed significant anti-arthritic
[109]
activity in an anti-collagen-induced rheumatoid arthritis mouse model . Moreover, preoperative
treatment of mice prior to lung transplantation improved early graft function and decreased active NSP
levels in the graft, indicating a novel potential use of cathepsin C inhibitors . Despite its promising
[110]
potential, there is currently no information on its further exploration as a candidate for human clinical
trials.