Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional Selectivity

Falgueyret, Jean‐Pierre; Desmarais, Sylvie; Oballa, Renata M.; Black, W. Cameron; Cromlish, Wanda; Khougaz, Karine; Lamontagne, Sonia; Massé, Frédéric; Riendeau, Denis; Toulmond, Sylvie; Percival, M. David

doi:10.1021/jm0504961

Cited by 142 publications

(132 citation statements)

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“…The first aim of this study was the isolation and application of antibodies towards cathepsin S that would circumvent specificity problems associated with small molecule approaches (5,(26)(27)(28). We developed a panel of murine monoclonal antibodies using recombinant mature human cathepsin S protein as immunogen.…”

Section: Resultsmentioning

confidence: 99%

“…However, as a result of close family homology, efforts to develop specific small molecule inhibitors towards cathepsin S and indeed other cathepsins have been hindered by the inability to achieve selectivity (45). Furthermore, side effects and toxicities may be further compounded by the accumulation of these inhibitors within the lysosomes (particularly in cathepsin-rich tissues such as the liver), where they reach concentrations exceeding selective IC 50 doses (27,28). Given the potential pitfalls with such small molecule inhibitors, the application of antibodies to antagonize cathepsin S may offer significant therapeutic potential for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

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Antibody-Mediated Inhibition of Cathepsin S Blocks Colorectal Tumor Invasion and Angiogenesis

Burden

Gormley

Jaquin

et al. 2009

Clinical Cancer Research

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Purpose: Cathepsin S is a cysteine protease that promotes the invasion of tumor and endothelial cells during cancer progression. Here we investigated the potential to target cathepsin S using an antagonistic antibody, Fsn0503, to block these tumorigenic effects. Experimental Design: A panel of monoclonal antibodies was raised to human cathepsin S. The effects of a selected antibody were subsequently determined using invasion and proteolysis assays. Endothelial cell tube formation and aorta sprouting assays were done to examine antiangiogenic effects. In vivo effects were also evaluated using HCT116 xenograft studies. Results: A selected cathepsin S antibody, Fsn0503, significantly blocked invasion of a range of tumor cell lines, most significantly HCT116 colorectal carcinoma cells, through inhibition of extracellular cathepsin S-mediated proteolysis. We subsequently found enhanced expression of cathepsin S in colorectal adenocarcinoma biopsies when compared with normal colon tissue. Moreover, Fsn0503 blocked endothelial cell capillary tube formation and aortic microvascular sprouting. We further showed that administration of Fsn0503 resulted in inhibition of tumor growth and neovascularization of HCT116 xenograft tumors. The lysosomal cysteine cathepsins encompass a family of closely related cysteine proteases, mediating a diverse range of proteolytic effects (1-4). However, an increasing body of evidence has shown the overexpression of a number of cysteine cathepsins in cancer (5-7). Significantly, these proteases are secreted into the tumor extracellular milieu, producing potent degradative effects on a broad range of extracellular matrix (ECM) components, including collagen and laminins (8-10). Further confirmation of these effects were provided in a murine model of sporadic pancreatic carcinogenesis (RIP1-Tag2), in which the genetic ablation of either cathepsin B or cathepsin S severally attenuated tumor invasion and angiogenesis, and cathepsin L or cathepsin B deficiency inhibited tumor proliferation (11). These observations highlight their potential as therapeutic targets in cancer treatment. Indeed, the application of synthetic broad-spectrum probes and combination therapies has successfully shown efficacy in vivo using various tumor models (12-15). However, given the roles that these proteases play in normal cellular homeostasis, an approach that selectively targets a specific cathepsin with limited normal tissue distribution may be more therapeutically attractive.Cathepsin S, unlike the ubiquitous cathepsin B and cathepsin L, exhibits a restricted tissue expression. It is found predominantly in lymphatic tissue, macrophages, and other professional antigenpresenting cells (16); mediating key steps in antigen presentation through cleavage of the invariant chain (17,18). However, the inappropriate expression of cathepsin S has also been observed in a range of tumors such as astrocytomas (19-21), prostate (22), hepatocellular (23), and pancreatic carcinomas (11). Crucially, evidence from the RIP1-T...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Inhibition of Cathepsin S Blocks Colorectal Tumor Invasion and Angiogenesis

Burden

Gormley

Jaquin

et al. 2009

Clinical Cancer Research

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“…Similar to AFG-495, L-235 exhibits lysosomotropic properties; that is, these compounds accumulate within acidic subcellular organelles such as lysosomes or the resorption lacunae. This feature may compromise selectivity of the CatKi in vivo by inhibiting other lysosomal cathepsins at the doses used in this study (19,20). Several cysteine cathepsins, particularly CatB, have been shown to be causally involved in the migration and invasion of tumor cells (26,27); the lysosomotropic property of L-235 may in part contribute to its anti-invasive activity in this model of bone metastasis as discussed below.…”

Section: Discussionmentioning

confidence: 97%

“…This compound inhibits human CatK with a Ki of 0.25 nmol/L, and is >4,000-fold selective against other human cathepsins L, B, and S (17). However, unlike ODN, L-235 shows relatively good potency against mouse (IC 50 ¼ 20 nmol/L) and rat (IC 50 ¼ 12 nmol/L) CatK activity (19,20). Efficacy of L-235 as a bone resorption inhibitor has been well established in rabbits, it inhibits rabbit CatK (IC 50 ¼ 0.5 nmol/L) and bone resorption in vitro by rabbit OCs (IC 50 ¼ 5 nmol/L; ref.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Duong

Wesolowski

Leung

et al. 2014

Molecular Cancer Therapeutics

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Cathepsin K (CatK) is essential for osteoclast-mediated bone resorption. CatK expression is also detected in breast cancer cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30, and 100 mg/kg, p.o., b.i.d.) or treatment regimen (30 mg/kg) was compared with the bisphosphonate zoledronic acid (ZOL, 7.5 mg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden, and local metastasis was evaluated by radiography through 42 days and ex vivo mCT and histology. IHC and RT-PCR confirmed the increases in CatK protein and mRNA levels in human breast cancer primary and metastatic tumors. In the experimental model of breast cancer bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72%, 75%, and 87% respectively, compared with ZOL by 86% versus intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29%, 40%, and 63%, respectively, compared with 56% by ZOL versus vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden was comparable in treatment versus preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatK inhibitor was more effective than ZOL in reducing breast cancer invasion. These data support the role of CatK in breast cancer skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer. Mol Cancer Ther; 13(12); 2898-909. Ó2014 AACR.

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“…(2)(3)(4)(5)(6)(7) Recent advances have led to the discovery of drugs that selectively inhibit either acid secretion (8)(9)(10) or catK activity. (2)(3)(4)(5)11,12) Some early catK inhibitors proved to have crossreactivity with other cathepsins, (5,13,14) and cutaneous adverse events were reported for one. (3,15) A highly selective catK inhibitor that affects osteoclast bone resorption activity without effects on other cell types, including osteoblasts, would be attractive as a treatment for osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

Eisman

Bone²,

Hosking

et al. 2010

Journal of Bone and Mineral Research

228

147

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The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased boneresorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between À2.0 and À3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n ¼ 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (À50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. ß

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Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional Selectivity

Cited by 142 publications

References 31 publications

Antibody-Mediated Inhibition of Cathepsin S Blocks Colorectal Tumor Invasion and Angiogenesis

Antibody-Mediated Inhibition of Cathepsin S Blocks Colorectal Tumor Invasion and Angiogenesis

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

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