Covalent and non-covalent reversible proteasome inhibition
The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-...
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Gespeichert in:
| Autor*in: |
Beck, Philipp [verfasserIn] Dubiella, Christian [verfasserIn] Groll, Michael [verfasserIn] |
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| Format: |
E-Artikel |
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| Erschienen: |
De Gruyter ; 2012 |
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| Schlagwörter: |
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| Umfang: |
20 |
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| Reproduktion: |
Walter de Gruyter Online Zeitschriften |
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| Übergeordnetes Werk: |
Enthalten in: Biological chemistry - Berlin [u.a.] : de Gruyter, 1996, 393(2012), 10 vom: 08. Sept., Seite 1101-1120 |
| Übergeordnetes Werk: |
volume:393 ; year:2012 ; number:10 ; day:08 ; month:09 ; pages:1101-1120 ; extent:20 |
| Links: |
|---|
| DOI / URN: |
10.1515/hsz-2012-0212 |
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NLEJ246932236 |
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| 520 | |a The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. | ||
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10.1515/hsz-2012-0212 doi artikel_Grundlieferung.pp (DE-627)NLEJ246932236 DE-627 ger DE-627 rakwb Beck, Philipp verfasserin aut Covalent and non-covalent reversible proteasome inhibition De Gruyter 2012 20 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. Walter de Gruyter Online Zeitschriften drug development inhibitor non-covalent reversible ubiquitin pathway Dubiella, Christian verfasserin aut Groll, Michael verfasserin aut Enthalten in Biological chemistry Berlin [u.a.] : de Gruyter, 1996 393(2012), 10 vom: 08. Sept., Seite 1101-1120 (DE-627)NLEJ248235095 (DE-600)1466062-3 1437-4315 nnns volume:393 year:2012 number:10 day:08 month:09 pages:1101-1120 extent:20 https://doi.org/10.1515/hsz-2012-0212 Deutschlandweit zugänglich GBV_USEFLAG_U ZDB-1-DGR GBV_NL_ARTICLE AR 393 2012 10 08 09 1101-1120 20 |
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10.1515/hsz-2012-0212 doi artikel_Grundlieferung.pp (DE-627)NLEJ246932236 DE-627 ger DE-627 rakwb Beck, Philipp verfasserin aut Covalent and non-covalent reversible proteasome inhibition De Gruyter 2012 20 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. Walter de Gruyter Online Zeitschriften drug development inhibitor non-covalent reversible ubiquitin pathway Dubiella, Christian verfasserin aut Groll, Michael verfasserin aut Enthalten in Biological chemistry Berlin [u.a.] : de Gruyter, 1996 393(2012), 10 vom: 08. Sept., Seite 1101-1120 (DE-627)NLEJ248235095 (DE-600)1466062-3 1437-4315 nnns volume:393 year:2012 number:10 day:08 month:09 pages:1101-1120 extent:20 https://doi.org/10.1515/hsz-2012-0212 Deutschlandweit zugänglich GBV_USEFLAG_U ZDB-1-DGR GBV_NL_ARTICLE AR 393 2012 10 08 09 1101-1120 20 |
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10.1515/hsz-2012-0212 doi artikel_Grundlieferung.pp (DE-627)NLEJ246932236 DE-627 ger DE-627 rakwb Beck, Philipp verfasserin aut Covalent and non-covalent reversible proteasome inhibition De Gruyter 2012 20 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. Walter de Gruyter Online Zeitschriften drug development inhibitor non-covalent reversible ubiquitin pathway Dubiella, Christian verfasserin aut Groll, Michael verfasserin aut Enthalten in Biological chemistry Berlin [u.a.] : de Gruyter, 1996 393(2012), 10 vom: 08. Sept., Seite 1101-1120 (DE-627)NLEJ248235095 (DE-600)1466062-3 1437-4315 nnns volume:393 year:2012 number:10 day:08 month:09 pages:1101-1120 extent:20 https://doi.org/10.1515/hsz-2012-0212 Deutschlandweit zugänglich GBV_USEFLAG_U ZDB-1-DGR GBV_NL_ARTICLE AR 393 2012 10 08 09 1101-1120 20 |
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10.1515/hsz-2012-0212 doi artikel_Grundlieferung.pp (DE-627)NLEJ246932236 DE-627 ger DE-627 rakwb Beck, Philipp verfasserin aut Covalent and non-covalent reversible proteasome inhibition De Gruyter 2012 20 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. Walter de Gruyter Online Zeitschriften drug development inhibitor non-covalent reversible ubiquitin pathway Dubiella, Christian verfasserin aut Groll, Michael verfasserin aut Enthalten in Biological chemistry Berlin [u.a.] : de Gruyter, 1996 393(2012), 10 vom: 08. Sept., Seite 1101-1120 (DE-627)NLEJ248235095 (DE-600)1466062-3 1437-4315 nnns volume:393 year:2012 number:10 day:08 month:09 pages:1101-1120 extent:20 https://doi.org/10.1515/hsz-2012-0212 Deutschlandweit zugänglich GBV_USEFLAG_U ZDB-1-DGR GBV_NL_ARTICLE AR 393 2012 10 08 09 1101-1120 20 |
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10.1515/hsz-2012-0212 doi artikel_Grundlieferung.pp (DE-627)NLEJ246932236 DE-627 ger DE-627 rakwb Beck, Philipp verfasserin aut Covalent and non-covalent reversible proteasome inhibition De Gruyter 2012 20 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. Walter de Gruyter Online Zeitschriften drug development inhibitor non-covalent reversible ubiquitin pathway Dubiella, Christian verfasserin aut Groll, Michael verfasserin aut Enthalten in Biological chemistry Berlin [u.a.] : de Gruyter, 1996 393(2012), 10 vom: 08. Sept., Seite 1101-1120 (DE-627)NLEJ248235095 (DE-600)1466062-3 1437-4315 nnns volume:393 year:2012 number:10 day:08 month:09 pages:1101-1120 extent:20 https://doi.org/10.1515/hsz-2012-0212 Deutschlandweit zugänglich GBV_USEFLAG_U ZDB-1-DGR GBV_NL_ARTICLE AR 393 2012 10 08 09 1101-1120 20 |
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The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. |
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The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. |
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The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade®) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">NLEJ246932236</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230506180013.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">220814s2012 xx |||||o 00| ||und c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1515/hsz-2012-0212</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">artikel_Grundlieferung.pp</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)NLEJ246932236</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Beck, Philipp</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Covalent and non-covalent reversible proteasome inhibition</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="b">De Gruyter</subfield><subfield code="c">2012</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">20</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. 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7.4010057 |