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Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes.

Löser R, Pietzsch J - Front Chem (2015)

Bottom Line: The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging.After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response.In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Dresden, Germany ; Department of Chemistry and Food Chemistry, Technische Universität Dresden Dresden, Germany.

ABSTRACT
Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

No MeSH data available.


Related in: MedlinePlus

Odanacatib, probably the first cysteine protease inhibitor that will enter the drug market.
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Figure 5: Odanacatib, probably the first cysteine protease inhibitor that will enter the drug market.

Mentions: Partly due to the employment of the aforementioned inhibitors as experimental tools, the perception about the biological functions of cysteine proteases, especially those of the cathepsins, has changed dramatically over the last 20 years and until today the involvement in a plethora of individual cellular processes has been revealed for almost every individual cathepsin (Brix et al., 2008; Reiser et al., 2010). An increased activity of the cysteine cathepsins, which can result from increased expression or a reduced level of their endogenous protein inhibitors, has implications in several pathologies (Katunuma, 2011). Consequently, the cysteine cathepsins became highly attractive targets to develop drugs for the treatment of systemic human diseases (Turk et al., 2003). These diseases include autoimmune and allergic disorders (Reiser et al., 2010; Löser, 2011; Perišic Nanut et al., 2014), cardiovascular diseases, osteoporosis and cancer. In light of the pivotal role of cathepsin K in the degradation of osseous collagen, inhibitors directed against this protease have been developed to treat osteoporosis (Novinec and Lenarčič, 2013a). These efforts will probably lead to the first cathepsin inhibitor, named odanacatib, that can be launched to the drug market (13; Figure 5). Odanacatib is a dipeptide-derived nitrile which targets selectively cathepsin K. This compound is currently in phase III clinical studies for osteoporosis treatment, e.g., the Long-Term Odanacatib Fracture Trial (LOFT) (Bone et al., 2015), and in various phase II and III clinical trials targeting metastatic bone disease in advanced-stage breast and prostate cancer (Onishi et al., 2010; Sturge et al., 2011)3,4,5. Its discovery has been summarized in Gauthier et al. (2008). The most salient structural features of odanacatib are the replacement of the P3 carbonyl oxygen by a trifluoromethyl group, fluorination at Cγ in the P2 leucine side chain and a cyclopropyl group that integrates the Cα atom in P1. The advantages of peptide bond replacement by trifluoroethylamines have been outlined in Bigotti et al. (2009). Side-chain fluorination intended to block oxidative metabolism at the methine group and introduction of the cyclopropyl group stabilizes the P2-P1 amide against metabolic hydrolysis (Gauthier et al., 2008).


Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes.

Löser R, Pietzsch J - Front Chem (2015)

Odanacatib, probably the first cysteine protease inhibitor that will enter the drug market.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477214&req=5

Figure 5: Odanacatib, probably the first cysteine protease inhibitor that will enter the drug market.
Mentions: Partly due to the employment of the aforementioned inhibitors as experimental tools, the perception about the biological functions of cysteine proteases, especially those of the cathepsins, has changed dramatically over the last 20 years and until today the involvement in a plethora of individual cellular processes has been revealed for almost every individual cathepsin (Brix et al., 2008; Reiser et al., 2010). An increased activity of the cysteine cathepsins, which can result from increased expression or a reduced level of their endogenous protein inhibitors, has implications in several pathologies (Katunuma, 2011). Consequently, the cysteine cathepsins became highly attractive targets to develop drugs for the treatment of systemic human diseases (Turk et al., 2003). These diseases include autoimmune and allergic disorders (Reiser et al., 2010; Löser, 2011; Perišic Nanut et al., 2014), cardiovascular diseases, osteoporosis and cancer. In light of the pivotal role of cathepsin K in the degradation of osseous collagen, inhibitors directed against this protease have been developed to treat osteoporosis (Novinec and Lenarčič, 2013a). These efforts will probably lead to the first cathepsin inhibitor, named odanacatib, that can be launched to the drug market (13; Figure 5). Odanacatib is a dipeptide-derived nitrile which targets selectively cathepsin K. This compound is currently in phase III clinical studies for osteoporosis treatment, e.g., the Long-Term Odanacatib Fracture Trial (LOFT) (Bone et al., 2015), and in various phase II and III clinical trials targeting metastatic bone disease in advanced-stage breast and prostate cancer (Onishi et al., 2010; Sturge et al., 2011)3,4,5. Its discovery has been summarized in Gauthier et al. (2008). The most salient structural features of odanacatib are the replacement of the P3 carbonyl oxygen by a trifluoromethyl group, fluorination at Cγ in the P2 leucine side chain and a cyclopropyl group that integrates the Cα atom in P1. The advantages of peptide bond replacement by trifluoroethylamines have been outlined in Bigotti et al. (2009). Side-chain fluorination intended to block oxidative metabolism at the methine group and introduction of the cyclopropyl group stabilizes the P2-P1 amide against metabolic hydrolysis (Gauthier et al., 2008).

Bottom Line: The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging.After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response.In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Dresden, Germany ; Department of Chemistry and Food Chemistry, Technische Universität Dresden Dresden, Germany.

ABSTRACT
Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

No MeSH data available.


Related in: MedlinePlus