Discovery and Early Clinical Development of Selective Immunoproteasome Inhibitors

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Jan 11

PMID 35011570

Authors

Christopher J Kirk

Tony Muchamuel

Jinhai Wang

R Andrea Fan

Affiliations

Soon will be listed here.

Abstract

Inhibitors of the proteolytic activity of the 20S proteasome have transformed the treatment of multiple B-cell malignancies. These agents have also been employed with success in the treatment of patients with autoimmune diseases and immune-mediated disorders. However, new agents are needed to fully unlock the potential of proteasome inhibitors as immunomodulatory drugs. The discovery that selective inhibitors of the immunoproteasome possess broad anti-inflammatory activity in preclinical models has led to the progression of multiple compounds to clinical trials. This review focuses on the anti-inflammatory potential of immunoproteasome inhibition and the early development of KZR-616, the first selective inhibitor of the immunoproteasome to reach clinical testing.

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References

Goetzke C, Ebstein F, Kallinich T . Role of Proteasomes in Inflammation. J Clin Med. 2021; 10(8). PMC: 8072576. DOI: 10.3390/jcm10081783. View

Ciechanover A . Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ. 2005; 12(9):1178-90. DOI: 10.1038/sj.cdd.4401692. View

Robak P, Robak T . Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later. Drugs R D. 2019; 19(2):73-92. PMC: 6544598. DOI: 10.1007/s40268-019-0269-9. View

Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M . Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12(5):431-40. DOI: 10.1016/S1470-2045(11)70081-X. View

Federspiel J, Codreanu S, Goyal S, Albertolle M, Lowe E, Teague J . Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells. Mol Cell Proteomics. 2016; 15(10):3233-3242. PMC: 5054346. DOI: 10.1074/mcp.M116.059709. View

Ishii T, Tanaka Y, Kawakami A, Saito K, Ichinose K, Fujii H . Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus. Mod Rheumatol. 2018; 28(6):986-992. DOI: 10.1080/14397595.2018.1432331. View

Adams J . The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004; 4(5):349-60. DOI: 10.1038/nrc1361. View

Jenkins T, Downey-Kopyscinski S, Fields J, Rahme G, Colley W, Israel M . Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein. Sci Rep. 2021; 11(1):10883. PMC: 8149845. DOI: 10.1038/s41598-021-90451-9. View

Alexander T, Cheng Q, Klotsche J, Khodadadi L, Waka A, Biesen R . Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. Eur J Immunol. 2018; 48(9):1573-1579. DOI: 10.1002/eji.201847492. View

10.

Zhang H, Huang L, Hou J, Zhou M, Huang X, Hu W . The short-term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis. Lupus. 2017; 26(9):952-958. DOI: 10.1177/0961203316686703. View

11.

Li J, Basler M, Alvarez G, Brunner T, Kirk C, Groettrup M . Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation. Kidney Int. 2017; 93(3):670-680. DOI: 10.1016/j.kint.2017.09.023. View

12.

King R, Peters J, Tugendreich S, Rolfe M, Hieter P, Kirschner M . A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell. 1995; 81(2):279-88. DOI: 10.1016/0092-8674(95)90338-0. View

13.

Zhou H, Aujay M, Bennett M, Dajee M, Demo S, Fang Y . Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem. 2009; 52(9):3028-38. DOI: 10.1021/jm801329v. View

14.

Alexander T, Sarfert R, Klotsche J, Kuhl A, Rubbert-Roth A, Lorenz H . The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis. 2015; 74(7):1474-8. PMC: 4484251. DOI: 10.1136/annrheumdis-2014-206016. View

15.

Parlati F, Lee S, Aujay M, Suzuki E, Levitsky K, Lorens J . Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009; 114(16):3439-47. DOI: 10.1182/blood-2009-05-223677. View

16.

Bross P, Kane R, Farrell A, Abraham S, Benson K, Brower M . Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res. 2004; 10(12 Pt 1):3954-64. DOI: 10.1158/1078-0432.CCR-03-0781. View

17.

Fan H, Angelo N, Warren J, Nathan C, Lin G . Oxathiazolones Selectively Inhibit the Human Immunoproteasome over the Constitutive Proteasome. ACS Med Chem Lett. 2014; 5(4):405-10. PMC: 4027612. DOI: 10.1021/ml400531d. View

18.

Hartono C, Chung M, Perlman A, Chevalier J, Serur D, Seshan S . Bortezomib for Reduction of Proteinuria in IgA Nephropathy. Kidney Int Rep. 2018; 3(4):861-866. PMC: 6035125. DOI: 10.1016/j.ekir.2018.03.001. View

19.

Wang Z, Yang J, Kirk C, Fang Y, Alsina M, Badros A . Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib. Drug Metab Dispos. 2012; 41(1):230-7. DOI: 10.1124/dmd.112.047662. View

20.

Fang Y, Johnson H, Anderl J, Muchamuel T, McMinn D, Morisseau C . Role of Epoxide Hydrolases and Cytochrome P450s on Metabolism of KZR-616, a First-in-Class Selective Inhibitor of the Immunoproteasome. Drug Metab Dispos. 2021; 49(9):810-821. DOI: 10.1124/dmd.120.000307. View