Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism

The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a t...

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Autores principales:	Jinhai Wang, Ying Fang, R. Andrea Fan, Christopher J. Kirk
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	proteasome proteasome inhibitors immunoproteasome immunoproteasome inhibitors epoxide hydrolases microsomal epoxide hydrolase Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0e5977f856364f8c9a66879a821db2e7
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spelling	oai:doaj.org-article:0e5977f856364f8c9a66879a821db2e72021-11-11T17:04:45ZProteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism10.3390/ijms2221115951422-00671661-6596https://doaj.org/article/0e5977f856364f8c9a66879a821db2e72021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11595https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.Jinhai WangYing FangR. Andrea FanChristopher J. KirkMDPI AGarticleproteasomeproteasome inhibitorsimmunoproteasomeimmunoproteasome inhibitorsepoxide hydrolasesmicrosomal epoxide hydrolaseBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11595, p 11595 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	proteasome proteasome inhibitors immunoproteasome immunoproteasome inhibitors epoxide hydrolases microsomal epoxide hydrolase Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	proteasome proteasome inhibitors immunoproteasome immunoproteasome inhibitors epoxide hydrolases microsomal epoxide hydrolase Biology (General) QH301-705.5 Chemistry QD1-999 Jinhai Wang Ying Fang R. Andrea Fan Christopher J. Kirk Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
description	The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.
format	article
author	Jinhai Wang Ying Fang R. Andrea Fan Christopher J. Kirk
author_facet	Jinhai Wang Ying Fang R. Andrea Fan Christopher J. Kirk
author_sort	Jinhai Wang
title	Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
title_short	Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
title_full	Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
title_fullStr	Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
title_full_unstemmed	Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
title_sort	proteasome inhibitors and their pharmacokinetics, pharmacodynamics, and metabolism
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0e5977f856364f8c9a66879a821db2e7
work_keys_str_mv	AT jinhaiwang proteasomeinhibitorsandtheirpharmacokineticspharmacodynamicsandmetabolism AT yingfang proteasomeinhibitorsandtheirpharmacokineticspharmacodynamicsandmetabolism AT randreafan proteasomeinhibitorsandtheirpharmacokineticspharmacodynamicsandmetabolism AT christopherjkirk proteasomeinhibitorsandtheirpharmacokineticspharmacodynamicsandmetabolism
_version_	1718432161361559552

Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism

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