Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
Autor: | R. Andrea Fan, Jinhai Wang, Ying Fang, Christopher J. Kirk |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Proteasome Endopeptidase Complex
QH301-705.5 proteasome inhibitors Antineoplastic Agents Review Pharmacology immunoproteasome inhibitors Catalysis Ixazomib Inorganic Chemistry chemistry.chemical_compound immunoproteasome Pharmacokinetics Neoplasms epoxide hydrolases medicine Animals Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy Bortezomib Organic Chemistry General Medicine Plasma cell neoplasm Carfilzomib Computer Science Applications Chemistry proteasome chemistry Proteasome Microsomal epoxide hydrolase Pharmacodynamics microsomal epoxide hydrolase medicine.drug |
Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 11595, p 11595 (2021) International Journal of Molecular Sciences |
ISSN: | 1661-6596 1422-0067 |
Popis: | 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. |
Databáze: | OpenAIRE |
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