Proteasome and Protease Inhibitors
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
The most frequently described and well-known proteasome inhibitor is bortezomib (Velcade®, PS-341), a dipeptide boronic acid analog with a broad antitumor activity in several cell lines and murine and human tumor models (19,36,42,46,47). It is the first proteasome inhibitor that has been approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMEA) for use in MM. Bortezomib specifically inhibits the proteasome pathway rapidly and in a reversible manner by binding directly to the β-5 subunit of the 20S complex, thereby blocking its enzymatic activity (48). Exposure to bortezomib in vitro leads to stabilization of several intracellular protein levels such as cyclin-dependent kinase inhibitors (e.g., p21) and proapoptotic Bik/NBK (49,50). Cells accumulate in the G2-M phase of the cell cycle and subsequently undergo apoptosis.
Pulmonary reactions to novel chemotherapeutic agents and biomolecules
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
The FDA recently approved the first proteasome inhibitor, bortezomib, for the treatment of multiple myeloma and mantle-cell lymphoma. Early studies did not suggest any lung toxicity, but a report in 2006 from Miyakoshi and colleagues described severe pulmonary complications in 4 of 13 Japanese patients treated for multiple myeloma.151 The clinical presentation was characterized by asthma-like symptoms and fever, followed by respiratory failure with pulmonary infiltrates. In three of the patients, respiratory failure developed after repeated administration of bortezomib, and corticosteroids resulted in improvement; one of those three still ultimately died of respiratory failure, and autopsy showed diffuse alveolar damage. The fourth patient developed pulmonary complications immediately after the first dose of bortezomib, showed no improvement after corticosteroids, and died of respiratory failure.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Although the proteasome is thus an essential component of cellular metabolism, drugs targeting this pathway—e.g., to prevent its upregulation in case of the above mentioned skeletal muscle atrophy—have been developed. The proteasome is also an important therapeutic target in cancer therapy (for a review of computational approaches for the discovery of human proteasome inhibitors see Guedes et al., 2016) because cancer cells such as myeloma cells produce a large amount of paraprotein. An example is bortezomib (opposite scheme) a proteasome inhibitor employed to treat patients with multiple myeloma, lymphoma, chronic lymphocytic leukemia, head and neck cancer, and prostate cancer (Mitchell, 2003). Bortezomib is a dipeptidyl boronic acid derivative (contains pyrazinoic acid, phenylalanine and leucine with boronic acid in its structure), approved by the FDA in 2003. It acts by reversibly targeting an active-site N-terminal threonine residue in the β5 subunit of the proteasome, and proteasome activity returns about 72 h after administration. Bortezomib-mediated proteasome inhibition blocks cell division and induces apoptosis via caspases. Furthermore, the inhibition acts on cancer cells by changes in regulator proteins controlling the cell cycle regulation and the activation of nuclear factor κ-B (NF-κB). NF-κB must be activated for a variety of important steps in the tumorigenic process such as angiogenesis, cell proliferation, and metastasis; for more details see Chen et al., 2011.
The power of proteasome inhibition in multiple myeloma
Published in Expert Review of Proteomics, 2018
Thomas A. Guerrero-Garcia, Sara Gandolfi, Jacob P. Laubach, Teru Hideshima, Dharminder Chauhan, Constantine Mitsiades, Kenneth C. Anderson, Paul G. Richardson
Understanding these discrepancies between proteasome inhibitors in terms of efficacy and activity in different combinations, as well as in terms of safety profile and toxicities of importance, is a key goal of ongoing research, which – as reviewed herein – is incorporating proteomics approaches to further our knowledge of proteasome inhibitor sensitivity and resistance. With greater appreciation of these issues, and of the different benefits afforded by the different proteasome inhibitors, we will be able to move toward an era of greater personalization of therapy, which may consequently enable us to achieve the ultimate goal of MM treatment – cure – in a greater proportion of patients. Further research on rational combinations, incorporating current and emerging targeted agents, may lead us toward an ‘R-CHOP’-like approach for MM, similar to this curative approach utilized for some lymphomas, of which proteasome inhibitors will undoubtedly be a key component.
Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: a patent review from 1998 to 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Mohd Imran, Shah Alam Khan, Ahmed Subeh Alshrari, Mahmoud Mudawi Eltahir Mudawi, Mohammed Kanan Alshammari, Aishah Ali Harshan, Noufah Aqeel Alshammari
The main challenge to discover the proteasome inhibitor is their selectivity against the proteasome of eukaryotic cells, for example, human and kinetoplastid proteasome (Figure 2). This selectivity can be achieved by identifying the differences in the architecture of the active site by CryoEM or understanding the proteasome/biological differences [26]. Some proteasome inhibitors (bortezomib and ixazomib) are in practice as anticancer agents, which principally affect the β5 subunit of the human proteasome [26,62]. Tyrosine kinase inhibitors (canertinib, sunitinib, axitinib, erlotinib, dasatinib, imatinib, nilotinib, sorafenib, lapatinib, and gefitinib), including PI3K inhibitors (dactolisib), have also been claimed as anti-kinetoplastid agents [63–81]. However, a recent study [40] reported that GSK3494245, a KSPI, was inactive against PI3Kδ. This suggests that the anti-leishmanial activity of PI3K inhibitors and KSPIs involve different mechanisms of action.
Proteasome inhibition for the treatment of glioblastoma
Published in Expert Opinion on Investigational Drugs, 2020
Patrick Roth, Warren P. Mason, Paul G. Richardson, Michael Weller
Bortezomib was identified from a screening of several boronic acid peptide small molecule analogues that were tested against a panel of tumor cell lines [32]. It acts as a reversible inhibitor of the proteasome’s chymotrypsin-like activity but has limited activity against the other enzymatic activities of the proteasome. Following extensive preclinical testing, the drug was the first proteasome inhibitor to enter clinical trials. Bortezomib was particularly active against multiple myeloma and was systemically investigated in early clinical studies followed by trials with larger patient cohorts in late and early relapse followed by newly-diagnosed disease. Upon successful completion of both phase 2 and phase 3 studies, the drug was approved by the FDA and other regulatory authorities for the treatment of patients with relapsed multiple myeloma [33–35] and later for patients with newly diagnosed disease [36]. Furthermore, the drug was subsequently approved for the treatment of patients with mantle cell lymphoma [37]. In contrast to its strong clinical activity against hematological malignancies as well as a substantial body of literature describing convincing anti-tumor activity in various preclinical models, bortezomib displayed minimal or no activity against solid tumors in larger trials [38]. Bortezomib is mainly metabolized through the liver. Side effects include nausea, diarrhea, fatigue, thrombocytopenia and peripheral neuropathy [39]. The latter may originate from a non-proteasome-dependent mechanism with nonselective binding properties of the drug, including serine proteases and other molecules [40].
Related Knowledge Centers
- Bortezomib
- P53
- Programmed Cell Death
- Proteasome
- Protein
- Neoplasm
- Cancer
- Apoptosis
- Multiple Myeloma
- Lactacystin