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Cathepsin K inhibitors for osteoporosis and potential off-target effects

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Pages 585-600 | Published online: 24 Apr 2009

Bibliography

  • Available from: www.iofbonehealth.org/health-professionals/about-osteoporosis/epidemiology.html
  • Wells G, Tugwell P, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:529-39
  • Stephenson J. FDA orders estrogen safety warnings: agency offers guidance for HRT use. Jama 2003;289:537-8
  • Kavanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci USA 2006;103:7829-34
  • Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009;360:53-62
  • Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61
  • Bilezikian JP. Osteonecrosis of the jaw–do bisphosphonates pose a risk? N Engl J Med 2006;355:2278-81
  • Van Den Wyngaert T, Huizing MT, Vermorken JB. Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315-22
  • Grey A. Emerging pharmacologic therapies for osteoporosis. Expert Opin Emerg Drugs 2007;12:493-508
  • Reid IR. Anti-resorptive therapies for osteoporosis. Semin Cell Dev Biol 2008
  • Hansdottir H. Raloxifene for older women: a review of the literature. Clin Interv Aging 2008;3:45-50
  • Cranney A, Tugwell P, Zytaruk N, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:540-51
  • Cranney A, Horsley T, O'Donnell S, et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007;1581-235
  • Brinckerhoff C. Joint destruction in arthritis: Metalloproteinases in the spotlight. Arthritis Rheum 1991;34:1073-5
  • Reynolds JJ. Collagenases and tissue inhibitors of metalloproteinases: a functional balance in tissue degradation. Oral Dis 1996;2:70-6
  • Vaes G. On the mechanism of bone resorption. The action of parathyroid hormone on the excretion and sythesis of lysosomal enzymes and on the extracellular release of acid by bone cells. J Cell Biol 1968;39:676
  • Delaisse JM, Eeckhout Y, Vaes G. Inhibition of bone resorption in culture by inhibitors of thiol proteinases. Biochem J 1980;15:365-8
  • Delaisse JM, Boyde A, Maconnachie E, et al. The effects of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts. Bone 1987;8:305-13
  • Delaisse JM, Eeckhout Y, Vaes G. In vitro and in vivo evidence for the involvement of cysteine proteinases in bone resorption. Biochem and Biophys Res Commun 1984;125:441-7
  • Hanada K, Tamai M, Yamagish M. Isolation and characterization of E-64, a new thiol protease inhibitor. Agric BiolChem 1978;42:523-8
  • Green GD, Shaw E. Peptidyl diazomethyl ketones are specific inactivators of thiol proteinases. J Biol Chem 1981;256:1923-8
  • Rifkin BR, Vernillo AT, Kleckner AR, et al. Cathepsin B and L activities in isolated osteoclasts. Biochem Biophys Res Commun 1991;179:63-9
  • Etherington DJ, Evans PJ. The action of cathepsin B and collagenolytic cathepsin in the degradation of collagen. Acta Biol Med Ger 1977;36:1555-63
  • Tezuka K, Tezuka Y, Maejima A, et al. Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem 1994;269:1106-9
  • Shi GP, Chapman HA, Bhairi SM, et al. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett 1995;357:129-34
  • Bromme D, Okamoto K. Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol Chem Hoppe Seyler 1995;376:379-84
  • Drake FH, Dodds RA, James IE, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996;271:12511-16
  • Brömme D, Okamoto K, Wang BB, Biroc S. Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts. Functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme. J Biol Chem 1996;271:2126-32
  • Bossard MJ, Tomaszek TT, Thompson SK, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 1996;271:12517-24
  • Kafienah W, Bromme D, Buttle DJ, et al. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J 1998;331:727-32
  • Garnero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 1998;273:32347-52
  • Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996;273:1236-8
  • Lecaille F, Bromme D, Lalmanach G. Biochemical properties and regulation of cathepsin K activity. Biochimie 2008;90:208-26
  • Bühling F, Gerber A, Häckel c, et al. Expression of cathepsin K in lung epithelial cells. Am J Respir Crit Care Med 1999;20:612-19
  • Tepel C, Bromme D, Herzog V, Brix K. Cathepsin K in thyroid epithelial cells: sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J Cell Sci 2000;113:4487-98
  • Hou WS, Li Z, Gordon RE, et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol 2001;159:2167-77
  • Buhling F, Waldburg N, Kruger S, et al. Expression of cathepsins B, H, K, L, and S during human fetal lung development. Dev Dyn 2002;225:14-21
  • Xia L, kilb J, Wex H, et al. Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption cathepsin K-activity by peptidyl vinyl sulfones. Biol Chem 1999;380:679-87
  • Mano H, Yuasa T, Kameda T, et al. Mammalian mature osteoclasts as estrogen target cells. Biochem Biophys Res Commun 1996;223:637-42
  • Furuyama N, Fujisawa Y. Regulation of collagenolytic cysteine protease synthesis by estrogen in osteoclasts. Steroids 2000;65:371-8
  • Parikka V, Lehenkari P, Sassi ML, et al. Estrogen reduces the depth of resorption pits by disturbing the organic bone matrix degradation activity of mature osteoclasts. Endocrinology 2001;142:5371-8
  • Fujisaki K, Tanabe N, Suzuki N, et al. Receptor activator of NF-kappaB ligand induces the expression of carbonic anhydrase II, cathepsin K, and matrix metalloproteinase-9 in osteoclast precursor RAW264.7 cells. Life Sci 2007;80:1311-18
  • Fields GB, Van Wart HE, Birkedal-Hansen H. Sequence specificity of human skin fibroblast collagenase. Evidence for the role of collagen structure in determining the collagenase cleavage site. J Biol Chem 1987;262:6221-6
  • Gelb BD, Brömme D, Desnick RJ. Pycnodysostosis: cathepsin K deficiency, In: Sriver CR, Beaudet, AL, Valle D, Sly WCS, editors, The Metabolic and Molecular Bases of Inherited Diseases. New York, St. Louis, San Francisco, a.o, McGraw-Hill. Inc., 2001. p. 3453-68
  • Everts V, Hou WS, Rialland X, et al. Cathepsin K deficiency in pycnodysostosis results in accumulation of non-digested phagocytosed collagen in fibroblasts. Calcif Tissue Int 2003;73:380-6
  • Hou WS, Li Z, Buttner FH, et al. Cleavage site specificity of cathepsin K toward cartilage proteoglycans and protease complex formation. Biol Chem 2003;384:891-7
  • Fuller K, Lawrence KM, Ross JL, et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 2008;42:200-11
  • Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 2008;83:172-6
  • Li Z, Hou WS, Escalante-Torres CR, et al. Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. J Biol Chem 2002;277:28669-76
  • Li Z, Yasuda Y, Li W, et al. Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J Biol Chem 2004;279:5470-9
  • Li Z, Kienetz M, Cherney MM, et al. The crystal and molecular structures of a cathepsin K:chondroitin sulfate complex. J Mol Biol 2008;383:78-91
  • Li Z, Hou WS, Bromme D. Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 2000;39:529-36
  • Yamashita DS, Dodds RA. Cathepsin K and the design of inhibitors of cathepsin K. Curr Pharm Des 2000;6:1-24
  • Lecaille F, Kaleta J, Bromme D. Human and parasitic papain-like cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design. Chem Rev 2002;102:4459-88
  • Cai J, Jamieson C, Moir J, Rankocic Z. Cathepsin K inhibitors. Expert Opin on Ther Patents 2005;15:33-48
  • Deaton DN, Tavares FX. Design of cathepsin K inhibitors for osteoporosis. Curr Top Med Chem 2005;5:1639-75
  • Yasuda Y, Kaleta J, Bromme D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 2005;57:973-93
  • Leung-Toung R, Zhao Y, Li W, et al. Thiol proteases: inhibitors and potential therapeutic targets. Curr Med Chem 2006;13:547-81
  • Vasiljeva O, Reinheckel T, Peters C, et al. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 2007;13:387-403
  • Kim TS, Tasker AS. Non-covalent cathepsin K inhibitors for the treatment of osteoporosis. Curr Top Med Chem 2006;6:355-60
  • Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 2006;5:785-99
  • Black WC, Percival MD. The consequences of lysosomotropism on the design of selective cathepsin K inhibitors. Chembiochem 2006;7:1525-35
  • Falgueyret JP, Desmarais S, Oballa R, et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J Med Chem 2005;48:7535-43
  • Li CS, Deschenes D, Desmarais S, et al. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg Med Chem Lett 2006;16:1985-9
  • Desmarais S, Black WC, Oballa R, et al. Effect of cathepsin k inhibitor basicity on in vivo off-target activities. Mol Pharmacol 2008;73:147-56
  • Grabowskal U, Chambers TJ, Shiroo M. Recent developments in cathepsin K inhibitor design. Curr Opin Drug Discov Devel 2005;8:619-30
  • Boyce BF, Xing L, Yao Z, et al. Future anti-catabolic therapeutic targets in bone disease. Ann N Y Acad Sci 2006;1068:447-57
  • Close P, Neuprez A, Reginster JY. Developments in the pharmacotherapeutic management of osteoporosis. Expert Opin Pharmacother 2006;7:1603-15
  • Sheridan C. Can ‘double blockbuster’ strengthen Amgen's backbone? Nat Biotechnol 2008;26:361-3
  • Adami S, Supronik J, Hala T, et al. Effect of one year treatment with the cathepsin-K inhibitor, balicatib,on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis (abstract). J Bone Miner Res 2006;21:S24
  • Papanastasiou P, Ortmann CE, Olson M, et al. Effect of three months treatment with the cathepsin-K inhibitor, Balicatib, on biochemical markers of bone turnover in postmenopausal women: evidence for uncoupling of bone resorption and bone formation. J Bone Miner Res 2006;21:S59
  • Runger TM, Quintanilla-Dieck MJ, Bhawan J. Role of cathepsin K in the turnover of the dermal extracellular matrix during scar formation. J Invest Dermatol 2007;127:293-7
  • Buhling F, Rocken C, Brasch F, et al. Pivotal role of cathepsin K in lung fibrosis. Am J Pathol 2004;164:2203-16
  • Peroni A, Zini A, Braga V, et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J Am Acad Dermatol 2008;59:125-9
  • Altmann E, Renaud J, Green J, et al. Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors. J Med Chem 2002;45:2352-4
  • Altmann E, Green J, Tintelnot-Blomley M. Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin K-investigating P1' substituents. Bioorg Med Chem Lett 2003;13:1997-2001
  • Teno N, Irie O, Miyake T, et al. New chemotypes for cathepsin K inhibitors. Bioorg Med Chem Lett 2008;18:2599-603
  • Yamashita DS, Marquis RW, Xie R, et al. Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J Med Chem 2006;49:1597-612
  • Kumar S, Dare L, Vasko-Moser JA, et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 2007;40:122-31
  • Available from: www.gsk-clinicalstudyregister.com
  • Barrett DG, Catalano JG, Deaton DN, et al. Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett 2004;14:2543-6
  • Barrett DG, Catalano JG, Deaton DN, et al. Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. Bioorg Med Chem Lett 2004;14:4897-902
  • Catalano JG, Deaton DN, Long ST, et al. Design of small molecule ketoamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett 2004;14:719-22
  • Catalano JG, Deaton DN, Furfine ES, et al. Exploration of the P1 SAR of aldehyde cathepsin K inhibitors. Bioorg Med Chem Lett 2004;14:275-8
  • Tavares FX, Deaton DN, Miller LR, Wright LL. Ketoamide-based inhibitors of cysteine protease, cathepsin K: P3 modifications. J Med Chem 2004;47:5057-68
  • Tavares FX, Deaton DN, Miller AB, et al. Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K. J Med Chem 2004;47:5049-56
  • Tavares FX, Boncek V, Deaton DN, et al. Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k. J Med Chem 2004;47:588-99
  • Tavares FX, Deaton DN, Miller AB, et al. Ketoheterocycle-based inhibitors of cathepsin K: a novel entry into the synthesis of peptidic ketoheterocycles. Bioorg Med Chem Lett 2005;15:3891-5
  • Barrett DG, Boncek VM, Catalano JG, et al. P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett 2005;15:3540-6
  • Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 2008;18:923-8
  • Riese RJ, Wolf P, Bromme D, et al. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity 1996;4:357-66
  • Riese RJ, Mitchell RN, Villadangos JA, et al. Cathepsin S activity regulates antigen presentation and immunity. J Clin Invest 1998;101:2351-63
  • Masarachia P, Pun S, Kimmel D. Bone effects of cathepsin K inhibitor in ovariectomized rhesus monkeys. J Bone Miner Res 2007;22:S126
  • Rodan SB, Duong LT. Cathepsin K - A new molecular target for osteoporosis. IBMS BoneKEy 2008;5:16-24
  • Available from: www.medivir.com, press releases issued 11/22/2007
  • Available from: www.medivir.com, press releases issued 02/09/2009
  • Wang D, Bromme D. Drug delivery strategies for cathepsin inhibitors in joint diseases. Expert Opin Drug Deliv 2005;2:1015-28
  • Quibell M, Benn A, Flinn N, et al. Bicyclic peptidomimetic tetrahydrofuro[3,2-b]pyrrol-3-one and hexahydrofuro[3,2-b]pyridine-3-one based scaffolds: synthesis and cysteinyl proteinase inhibition. Bioorg Med Chem 2004;12:5689-710
  • Quibell M, Benn A, Flinn N, et al. Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases. Bioorg Med Chem 2005;13:609-25
  • Available from: www.amura.co.uk
  • Dejica VM, Mort JS, Laverty S, et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am J Pathol 2008;173:161-9
  • Vinardell T, Dejica V, Poole AR, et al. Evidence to suggest that cathepsin K degrades articular cartilage in naturally occurring equine osteoarthritis. Osteoarthritis Cartilage 2009;17:375-83
  • Quintanilla-Dieck MJ, Codriansky K, Keady M, et al. Cathepsin K in melanoma invasion. J Invest Dermatol 2008;128:2281-8
  • Bone HG, Mcclung M, Verbruggen N, et al. A randomized double-blind, placibo-controlled study of cathepsin K inhibitor in the treatment of postmenopausal women with low BMD: one year results. J Bone Miner Res 2008;22:S37
  • Friedrichs B, Tepel C, Reinheckel T, et al. Thyroid functions of mouse cathepsins B, K, and L. J Clin Invest 2003;111:1733-45
  • Sirbulescu R, Jordans S, Lerchl A, et al. Trafficking of cysteine cathepsins to the extracellular thyroid follicle lumen helps mice to improve their memory and learning skills, Xth. International symposium on proteinase inhibitors and biological control. Portoroz, Slovenia, June 23-27, 2007
  • Rivas M, Naranjo JR. Thyroid hormones, learning and memory. Genes Brain Behav 2007;6 (Suppl 1):40-4
  • Bernstein HG, Bukowska A, Dobrowolny H, et al. Cathepsin K and schizophrenia. Synapse 2007;61:252-3
  • Bhoola KD, Elson CJ, Dieppe PA. Kinins–key mediators in inflammatory arthritis? Br J Rheumatol 1992;31:509-18
  • Veillard F, Lecaille F, Lalmanach G. Lung cysteine cathepsins: intruders or unorthodox contributors to the kallikrein-kinin system? Int J Biochem Cell Biol 2008;40:1079-94
  • Desmazes C, Galineau L, Gauthier F, et al. Kininogen-derived peptides for investigating the putative vasoactive properties of human cathepsins K and L. Eur J Biochem 2003;270:171-8
  • Godat E, Lecaille F, Desmazes C, et al. Cathepsin K: a cysteine protease with unique kinin-degrading properties. Biochem J 2004;383:501-6
  • Desmazes C, Gauthier F, Lalmanach G. Cathepsin L, but not cathepsin B, is a potential kininogenase. Biol Chem 2001;382:811-15
  • Lecaille F, Vandier C, Godat E, et al. Modulation of hypotensive effects of kinins by cathepsin K. Arch Biochem Biophys 2007;459:129-36
  • Lecaille F, Chowdhury S, Purisima E, et al. The S2 subsites of cathepsins K and L and their contribution to collagen degradation. Protein Sci 2007;16:662-70
  • Wall E, Walker-Bone K. Use of bisphosphonates and dual-energy X-ray absorptiometry scans in the prevention and treatment of glucocorticoid-induced osteoporosis in rheumatology. Qjm 2008;101:317-23
  • Morko J, Kiviranta R, Joronen K, et al. Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K. Arthritis Rheum 2005;52:3713-17
  • Hou WS, Li W, Keyszer G, et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 2002;46:663-74
  • Konttinen YT, Mandelin J, Li TF, et al. Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis. Arthritis Rheum 2002;46:953-60
  • Weidauer E, Yasuda Y, Biswal BS, et al. Effects of DMARDs on the activities of rheumatoid arthritis associate cathepsin K and S. Biol Chem 2007;388:331-6
  • Schurigt U, Hummel KM, Petrow PK, et al. Cathepsin K deficiency partially inhibits, but does not prevent, bone destruction in human tumor necrosis factor-transgenic mice. Arthritis Rheum 2008;58:422-34
  • Furuyama N, Fujisawa Y. Distinct roles of cathepsin K and cathepsin L in osteoclastic bone resorption. Endocr Res 2000;26:189-204
  • Saftig P, Wehmeyer O, Hunziker E, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin K-deficient mice. Proc Natl Acad Sci USA 1998;95:13453-8
  • Salminen-Mankonen HJ, Morko J, Vuorio E. Role of cathepsin K in normal joints and in the development of arthritis. Curr Drug Targets 2007;8:315-23
  • Morko JP, Soderstrom M, Saamanen AM, et al. Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis. Ann Rheum Dis 2004;63:649-55
  • Lutgens E, Lutgens SP, Faber BC, et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 2006;113:98-107
  • Samokhin AO, Wong A, Saftig P, Bromme D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 2008;200:58-68
  • Jackson CL. Defining and defending murine models of plaque rupture. Arterioscler Thromb Vasc Biol 2007;27:973-7
  • Liu J, Sukhova GK, Sun JS, et al. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:1359-66
  • Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. Faseb J 2007;21:3029-41
  • Taleb S, Clement K. Emerging role of cathepsin S in obesity and its associated diseases. Clin Chem Lab Med 2007;45:328-32
  • Taleb S, Lacasa D, Bastard JP, et al. Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis. Faseb J 2005;19:1540-2
  • Rodgers KJ, Watkins DJ, Miller AL, et al. Destabilizing role of cathepsin S in murine atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2006;26:851-6
  • Nadler ST, Stoehr JP, Schueler KL, et al. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc Natl Acad Sci USA 2000;97:11371-6
  • Chiellini C, Costa M, Novelli SE, et al. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J Cell Physiol 2003;195:309-21
  • Xiao Y, Junfeng H, Tianhong L, et al. Cathepsin K in adipocyte differentiation and its potential role in the pathogenesis of obesity. J Clin Endocrinol Metab 2006;91:4520-7
  • Funicello M, Novelli M, Ragni M, et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS ONE 2007;2:e683
  • Berdowska I. Cysteine proteases as disease markers. Clin Chim Acta 2004;342:41-69
  • Mohamed MM, Sloane BF. Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 2006;6:764-75
  • Palermo C, Joyce JA. Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci 2008;29:22-8
  • Kos J, Werle B, Lah T, Brunner N. Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer. Int J Biol Markers 2000;15:84-9
  • Jedeszko C, Sloane BF. Cysteine cathepsins in human cancer. Biol Chem 2004;385:1017-27
  • Littlewood-Evans AJ, Bilbe G, Bowler WB, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 1997;57:5386-90
  • Gaumann A, Hansen T, Kohler HH, et al. The expression of cathepsins in osteoclast-like giant cells of an anaplastic thyroid carcinoma with tracheal perforation. Pathol Res Pract 2001;197:257-62
  • Brubaker KD, Vessella RL, True LD, et al. Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res 2003;18:222-30
  • Lindeman JH, Hanemaaijer R, Mulder A, et al. Cathepsin K is the principal protease in giant cell tumor of bone. Am J Pathol 2004;165:593-600
  • Rapa I, Volante M, Cappia S, et al. Cathepsin K is selectively expressed in the stroma of lung adenocarcinoma but not in bronchioloalveolar carcinoma. A useful marker of invasive growth. Am J Clin Pathol 2006;125:847-54
  • Podgorski I, Linebaugh BE, Sloane BF. Cathepsin K in the bone microenvironment: link between obesity and prostate cancer? Biochem Soc Trans 2007;35:701-3
  • Available from: www.merck.com/newsroom/press_releases/research_and_development/2008_0527.html
  • Wang Y, benn A, Flinn N, et al. cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole based scaffolds: design rationale, synthesis and cysteinyl proteinase inhibition. Bioorg Med Chem Lett 2005;15:1327-31
  • Palmer JT, Rasnick D, Klaus JL, Brömme D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem 1995;38:3193-6

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