The identification of potent, selective, and bioavailable cathepsin S inhibitors

Gauthier, Jacques Yves; Black, W. Cameron; Courchesne, Isabelle; Cromlish, Wanda; Desmarais, Sylvie; Houle, Robert; Lamontagne, Sonia; Li, Chun Sing; Massé, Frédéric; McKay, Daniel J.; Ouellet, Marc; Robichaud, Jacques; Truchon, Jean‐Francois; Truong, Vouy-Linh; Wang, Qingping; Percival, M. David

doi:10.1016/j.bmcl.2007.06.023

Cited by 56 publications

(72 citation statements)

References 9 publications

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“…They gain antigen-presenting capacities and secrete the protease CATS. Regulating the expression of CATS by either anticytokine therapy (72) or the recently developed CATS-inhibitors (73)(74)(75) could represent important strategies for the therapy of psoriasis. IFNg and TNFa work both upstream to CATS, but TNAa inhibitors cause severe side effects in some patients (76,77).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of cathepsin S in psoriatic keratinocytes

Schönefuß

Wendt

Schattling

et al. 2010

Experimental Dermatology

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Cathepsin S (CATS) is a cysteine protease, well known for its role in MHC class II-mediated antigen presentation and extracellular matrix degradation. Disturbance of the expression or metabolism of this protease is a concomitant feature of several diseases. Given this importance we studied the localization and regulation of CATS expression in normal and pathological human ⁄ mouse skin. In normal human skin CATSimmunostaining is mainly present in the dermis and is localized in macrophages, Langerhans, T-and endothelial cells, but absent in keratinocytes. In all analyzed pathological skin biopsies, i.e. atopic dermatitis, actinic keratosis and psoriasis, CATS staining is strongly increased in the dermis. But only in psoriasis, CATSimmunostaining is also detectable in keratinocytes. We show that cocultivation with T-cells as well as treatment with cytokines can trigger expression and secretion of CATS, which is involved in MHC II processing in keratinocytes. Our data provide first evidence that CATS expression (i) is selectively induced in psoriatic keratinocytes, (ii) is triggered by T-cells and (iii) might be involved in keratinocytic MHC class II expression, the processing of the MHC class II-associated invariant chain and remodeling of the extracellular matrix. This paper expands our knowledge on the important role of keratinocytes in dermatological disease.

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Section: Discussionmentioning

confidence: 99%

Upregulation of cathepsin S in psoriatic keratinocytes

Schönefuß

Wendt

Schattling

et al. 2010

Experimental Dermatology

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“…To gain some understand- ing of the mechanism underlying the increase in Cat B and L protein in the tissues of L-006235 and balicatib-treated rats, further studies were performed using the human monocytic THP-1 cell line and the highly selective cell-permeable Cat S inhibitor Cmpd B (Gauthier et al, 2007). This inhibitor was chosen for these in vitro experiments because a potent and selective nonbasic Cat B or L inhibitor was not available.…”

Section: Off-target Inhibition Of Basic Cathepsin K Inhibitorsmentioning

confidence: 99%

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Desmarais

Black²,

Oballa³

et al. 2007

Mol Pharmacol

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Cathepsin K is a lysosomal cysteine protease that is a pharmacological target for the treatment of osteoporosis. Previous studies showed that basic, lipophilic cathepsin K inhibitors are lysosomotropic and have greater activities in cell-based assays against cathepsin K, as well as the physiologically important lysosomal cysteine cathepsins B, L, and S, than expected based on their potencies against these isolated enzymes. Long-term administration of the basic cathepsin K inhibitors N- (1-(((cyanomethyl) -006235) and balicatib to rats at a supratherapeutic dose of 500 mg/kg/day for 4 weeks resulted in increased tissue protein levels of cathepsin B and L but had no effect on cathepsin B and L message. This is attributed to the inhibitor engagement of these off-target enzymes and their stabilization to proteolytic degradation. No such increase in these tissue cathepsins was detected at the same dose of, a potent nonbasic cathepsin K inhibitor with a similar off-target profile, although all three inhibitors provided similar plasma exposures. Using an activity-based probe, 125 I-BIL-DMK, in vivo inhibition of cathepsins B, L, and S was detected in tissues of mice given a single oral dose of L-006235 and balicatib, but not in mice given L-873724. In each case, similar tissue levels were achieved by all three compounds, thereby demonstrating the in vivo cathepsin selectivity of L-873724. In conclusion, basic cathepsin K inhibitors demonstrate increased off-target cysteine cathepsin activities than their nonbasic analogs and potentially have a greater risk of adverse effects associated with inhibition of these cathepsins.The CA1 family of human papain-like cysteine proteases comprises 11 members. These enzymes are collectively known as cathepsins, a name which is derived from the Greek kathepsein, to digest. Being largely lysosomal enzymes, cathepsins have acidic pH activity and stability optima. These enzymes are synthesized as preproenzymes, the mature proteins sharing between 25 and 80% sequence identity (Lecaille et al., 2002;Turk et al., 2003). Cathepsin K (Cat K) is highly and somewhat specifically expressed in osteoclasts, the multinucleated giant cells of hematopoietic origin that are responsible for the normal physiological process of bone resorption. Cat K destroys the organic fraction of bone through its potent collagenase activity, this process taking place in the acidic pit between the osteoclast and the bone surface and also intracellularly within lysosomes of the osteoclast (Saftig et al., 1998). A large volume of genetic and pharmacological data points to a pivotal role for Cat K in bone resorption, and Cat K inhibitors are presently being evaluated in clinical trials as a treatment of osteoporosis, a disease characterized by an imbalance of bone resorption over bone formation (performed by osteoblasts) (Deaton and Tavares, 2005;Grabowskal et al., 2005;Yasuda et al., 2005;Boyce et al., 2006;Close et al., 2006). Both physiological and pathological roles have been identified for the remaining 10 ...

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“…CatS-inhibitors are currently being pursued for the treatment of rheumatoid arthritis, itch and psoriasis [39] with two compounds, RWJ-445380 and CRA-028129, in late stage clinical trial for the treatment of rheumatoid arthritis and psoriasis. CatS-inhibitor 5 [40] was also reported to reduce artherosclerosis [41] in a mouse model. Recently, a new class of highly selective CatS-inhibitors based on a pyrrolidine-scaffold were reported with favourable in vivo properties (Figure 2b, 6) [42 ].…”

Section: Proteases In Invariant Chain Maturationmentioning

confidence: 92%