Identification of a potent and selective non-basic cathepsin K inhibitor

Li, Chun Sing; Deschênes, Denis; Desmarais, Sylvie; Falgueyret, Jean‐Pierre; Gauthier, Jacques Yves; Kimmel, Donald B.; Léger, Serge; Massé, Frédéric; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Thérien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. Cameron

doi:10.1016/j.bmcl.2005.12.071

Cited by 79 publications

(35 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The tissue levels of mice dosed with L-006235, balicatib, and Cmpd A were approximately 5-to 10-fold higher than those attained in plasma, consistent with their lysosomotropic properties and previous tissue level studies in rats (Falgueyret et al, 2005). In contrast, plasma and tissue levels of L-873724 were similar, consistent with its volume of distribution of around unity and nonbasic nature (Li et al, 2006). Comparison of SDS-PAGE autoradiograms of tissue lysates from vehicle-, L-006235-, and balicatib-treated animals show that Cat B, L, and S labeling was consistently competed in each organ by the basic inhibitors.…”

Section: Evaluation Of In Vivo Cathepsin Inhibition Profilesupporting

confidence: 85%

See 1 more Smart Citation

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

Desmarais

Black²,

Oballa³

et al. 2007

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

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 ...

show abstract

Section: Evaluation Of In Vivo Cathepsin Inhibition Profilesupporting

confidence: 85%

“…The profiles of these inhibitors were compared with that of a nonbasic Cat K inhibitor, L-873724 ( Fig. 1) (Li et al, 2006). We examined whether chronic treatment of rats with a high dose of these Cat K inhibitors caused a perturbation of tissue enzyme levels compared with vehicle-treated animals.…”

mentioning

confidence: 99%

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

Desmarais

Black²,

Oballa³

et al. 2007

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…CA074 was purchased from Peptides International (Louisville, KY). Cathepsin K inhibitor L-873724 29 was obtained from (Merck-Frosst, Canada). Mouse anti-human cathepsin K antibodies were purchased from Novocastra (Newcastle, UK).…”

Section: Methodsmentioning

confidence: 99%

“…29 Immunoblot analysis using antibodies against full length SPARC showed that inhibition of cathepsin K did not have a significant effect on intracellular levels of this protein ( Figure 7A, Lysates, top panel). However, a significant reduction in the levels of secreted SPARC and disappearance of the 40-kDa band, indicative of reduced enzymatic processing, were observed in the presence of the cathepsin K inhibitor ( Figure 7A, media, top panel).…”

Section: Effect Of Cathepsin K Inhibition On Enzymatic Processing Of mentioning

confidence: 99%

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Podgorski

Linebaugh

Koblinski

et al. 2009

The American Journal of Pathology

View full text Add to dashboard Cite

Prostate and breast cancers commonly metastasize to skeletal sites and locally disrupt normal bone remodeling.Despite recent progress in cancer detection and treatment, it remains unclear which skeletal-specific factors are among the critical determinants in preferential localization of metastatic cells to the bone. Recent clinical and experimental data suggest that accelerated bone remodeling may be responsible for homing of tumor cells to the bone.1,2 This is evidenced by the increased metastasis in response to experimental treatment with calciotropic hormone or to androgen ablation 1,2 and reduced incidence of metastasis with antiresorptive therapies.3 Establishment of tumors in bone requires multidirectional interactions between tumor cells, bone cells, stromal cells, and inflammatory components, as well as extracellular matrix proteins. This complex interplay between tumor cells and the bone microenvironment facilitates increased bone turnover and promotes tumor cell survival.The key enzyme responsible for osteolysis of bone is the cysteine protease cathepsin K, which is the only known mammalian protease capable of degrading both the helical and non-helical regions of collagen I, the main component of the organic bone matrix. 4 Within the bone microenvironment, cathepsin K localizes predominantly to osteoclasts and its overexpression results in increased bone turnover.5 Accordingly, a deficiency in this potent collagenase results in a bone-sclerosing disorder called pycnodysostosis in man and osteopetrosis in mice. 6,7 The presence of cathepsin K has been demonstrated in many malignancies including prostate and breast cancers, both of which have a high propensity to metastasize to bone. 8 -10 A role for cathepsin K in advanced cancers has been attributed mainly to its ability to degrade native collagen I and facilitate the expansion of tumors in the bone. Our recent studies and data by other groups suggest that cathepsin K also cleaves and thereby modulates the biological activity of several important proteins in the bone microenvironment.11-15 Of particular importance is Supported by grants from the DOD PC030325. DOD PC074031. DOD

show abstract

“…The reaction was stopped by the addition of a specific cysteine protease inhibitor, E-64 (Peptide International, Louisville, KY), at a final concentration of 50 mol/L. Two other digestions were performed at pH 5.5, in the absence and presence of a potent and selective nonbasic cathepsin K inhibitor, 19 L-873724 (Merck Frosst, Kirkland, Canada). Digestions at pH 7.0 in the presence of 2 mol/L cathepsin K were used to determine the time-dependent release of the epitope at 0, 3, 24, and 48 hours, in the absence or presence of chondroitin-4 sulfate or chondroitin-6 sulfate (chondroitin sulfate C, Sigma).…”

Section: Digestion Of Human Col II With Cathepsin K Mmp-13 and Mmp-3mentioning

confidence: 99%

Cleavage of Type II Collagen by Cathepsin K in Human Osteoarthritic Cartilage

Dejica

Mort

Laverty

et al. 2008

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Cathepsin K is a cysteine protease of the papain family that cleaves triple-helical type II collagen, the major structural component of the extracellular matrix of articular cartilage. In osteoarthritis (OA), the anabolic/catabolic balance of articular cartilage is disrupted with the excessive cleavage of collagen II by collagenases or matrix metalloproteinases. A polyclonal antibody against a C-terminal neoepitope (C2K) generated in triple-helical type II collagen by the proteolytic action of cathepsin K was prepared and used to develop an enzyme-linked immunosorbent assay to study the generation of this epitope and the effects of its presence in normal adult and osteoarthritic femoral condylar articular cartilage. The generation of the C2K epitope in explant culture and the effect of a specific cathepsin K inhibitor were studied. The neoepitope, which is not generated by the collagenase matrix metalloproteinase-13, increased with age in articular cartilage and was significantly elevated in osteoarthritic cartilage compared with adult nonarthritic cartilage. Moreover, in explants from three of eight OA patients, the generation of the neoepitope in culture was significantly reduced by a specific, nontoxic inhibitor of cathepsin K. These data suggest that cathepsin K is involved in the cleavage of type II collagen in human articular cartilage in certain OA patients and that it may play a role in both OA pathophysiology and the aging process. Type II collagen (Col II), the major structural component of the extracellular matrix of articular cartilage, is composed of three identical ␣ chains that form a triple helix. These molecules self-associate to form the collagen fibrils, which are stabilized by intermolecular crosslinks. In osteoarthritis (OA), the anabolic/catabolic balance of articular cartilage is disrupted with excessive cleavage of Col II involving collagenases, which are matrix metalloproteinases or MMPs.

show abstract

Identification of a potent and selective non-basic cathepsin K inhibitor

Cited by 79 publications

References 12 publications

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

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

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Cleavage of Type II Collagen by Cathepsin K in Human Osteoarthritic Cartilage

Contact Info

Product

Resources

About