Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity

Baugh, Mark; Black, D. StC.; Westwood, Paul; Kinghorn, Emma; McGregor, Kieran; Bruin, John; Hamilton, William; Dempster, Maureen; Claxton, Christopher; Cai, Jiaqiang; Bennett, Jonathan; Long, Clive; McKinnon, Heather J.; Vink, Paul; Hoed, Leontien den; Górecka, Monika; Vora, Kalpit A.; Grant, Ethan P.; Percival, M. David; Boots, A.; Lierop, Marie-José van

doi:10.1016/j.jaut.2011.01.003

Cited by 62 publications

(43 citation statements)

References 42 publications

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“…The causative effect of the protease was further demonstrated in this model, revealing reduced progress of the disease in the absence of the protease species (Nakagawa et al, 1999). The pharmacological relevance of this expression of cathepsin S was revealed using an experimental inhibitor, CSI-75, which reduced disease scoring and disease progression (Baugh et al, 2011). In humans, similar trends of elevated cathepsin S levels are observed with plasma in patients with rheumatoid arthritis in comparison to normal healthy controls (Ruge et al, 2014).…”

Section: Autoimmune Diseasesmentioning

confidence: 62%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

161

139

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Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.

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Section: Autoimmune Diseasesmentioning

confidence: 62%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

161

139

View full text Add to dashboard Cite

show abstract

“…Further pharmacogenetic analysis, evaluating a genetic basis for relapsing MS patients who response to glatiramer acetate immunotherapy, also identified an associated SNP in the catS gene [65]. These studies have been further complemented by the observation that the inhibition of CatS in the experimental autoimmune encephalomyelitis (EAE) model has demonstrated a suppression of the MS-like condition in vivo [59].…”

Section: Autoimmune Disordersmentioning

confidence: 98%

“…Collectively, these findings underpin that CatS plays a key role in RA via ECM degradation and synovial destruction, leading to cartilage depletion, and represents a valid therapeutic target to alleviate the disease. Indeed, a CatS-specific inhibitor has recently been shown to reduce disease progression in the murine model of AIA [59].…”

Section: Autoimmune Disordersmentioning

confidence: 99%

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Small

Burden

Scott

2011

Clinic Rev Bone Miner Metab

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Cathepsin S is a lysosomal cysteine protease that has been shown to play a key role in MHC class II antigen presentation. Consequently, it has been extensively evaluated as a therapeutic target in autoimmune diseases, such as rheumatoid arthritis and psoriasis. Additionally, clinical and mechanistic evidence is emerging, revealing its inappropriate expression and secretion in a wide range of disease states including atherosclerosis and tumourigenesis. This review covers the known role and consequences of cathepsin S activity in these pathological disorders, highlighting various studies that have demonstrated its utility as a therapeutic target. This review also examines challenges that exist towards the development of agents that specifically target this protease and discusses the studies to date that have applied cathepsin S inhibitors in disease models.

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“…As described above cysteine cathepsin-specific inhibitors were applied successfully in several animal models of human RA [58,88,89,92,93]. The reduction of disease severity was observed.…”

Section: Animal Models Of Ramentioning

confidence: 97%

“…Cathepsin S-deficient mice develop a diminished CIA probably caused by influences of cathepsin S to late stages of Li degradation in APCs and influencing the peptide repertoire displayed by MHC class II molecules [62] (Table 1). Therapeutic applications of a highly selective and oral available cathepsin S inhibitor reduced significantly the disease score in arthritic CIA mice [93]. The development of further new cathepsin Sspecific inhibitors may be useful in treatment of human RA and other autoimmune diseases.…”

Section: Animal Models Of Ramentioning

confidence: 98%

Role of Cysteine Cathepsins in Joint Inflammation and Destruction in Human Rheumatoid Arthritis and Associated Animal Models

Schurigt¹

2013

Innovative Rheumatology

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Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity

Cited by 62 publications

References 42 publications

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S: therapeutic, diagnostic, and prognostic potential

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Role of Cysteine Cathepsins in Joint Inflammation and Destruction in Human Rheumatoid Arthritis and Associated Animal Models

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