Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases - PubMed (original) (raw)

Review

Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases

Mariola J Edelmann et al. Expert Rev Mol Med. 2011.

Free PMC article

Abstract

Recent advances in the development and discovery of pharmacological interventions within the ubiquitin-proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection.

PubMed Disclaimer

Figures

Figure 1

Small-molecule inhibitors in the ubiquitin–proteasome system (UPS). Schematic representation of components of the UPS including E1, E2–E3 ligases, DUBs and the proteasome complex (20Si: immunoproteasome). Ubiquitin is indicated as pink circle labelled U. The UPS pathway and different examples of E1, E2, E3s and DUBs are highlighted in blue boxes. Increasing numbers of small-molecule inhibitors that interfere at various steps of the UPS cascade are being discovered.

Figure 2

Small-molecule inhibitors against deubiquitylating enzymes. Examples of DUB inhibitors characterised in the literature targeting the USP family: HBX41,108 (1) (Ref. 50) and P022077 (2) (Ref. 51) specific for USP7, HBX 90,397 inhibits USP8 (3) (Ref. 52) and IU1 (7) inhibits USP14 (Ref. 53). Inhibitors targeting the UCH family include 15d-PGJ2 (Ref. 54) (4) and isatin _O_-acyl oximes (5) (Ref. 55) specific against UCH-L3 and other isatin derivatives (6) specific against UCH-L1 (Refs 56, 57). PR-619 (6) targets a broad range of DUBs (Ref. 51) and GRL0617 (9) inhibits SARS virus encoded papain-like protease (PLpro) (Ref. 58).

Figure 3

Small-molecule inhibitors against ubiquitin/Ubl-conjugating enzymes. Examples of inhibitors against E3 ligases include Nutlin-3a (10), RITA (11), MI-219 (12), JNJ-26854165 (13), chlorofusin (14) and chalcone (AM114) (15), which specifically interfere with the HDM2–p53 or HDM2–proteasome interactions (Refs 88, 89, 90, 91, 92, 93), and thalidomide (16), which inhibits CRBN (Ref. 94). The ubiquitin-activating enzyme E1 is targeted by PYR-41 (Ref. 95) (17), and the NEDD8-activating enzyme NAE1 is inhibited by MLN4924 (18) (Ref. 96). All molecular targets are associated with disease pathologies, in particular cancer. See text for further details. Abbreviations: CRBN, cereblon; NEDD8, neural precursor cell expressed developmentally down-regulated 8; Ubl, ubiquitin-like protein.

Cited by

Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome.
Tomaić V, Banks L. Tomaić V, et al. Cell Death Dis. 2015 Jan 29;6(1):e1625. doi: 10.1038/cddis.2014.572. Cell Death Dis. 2015. PMID: 25633294 Free PMC article.
Molecular mechanisms of acquired proteasome inhibitor resistance.
Kale AJ, Moore BS. Kale AJ, et al. J Med Chem. 2012 Dec 13;55(23):10317-27. doi: 10.1021/jm300434z. Epub 2012 Oct 3. J Med Chem. 2012. PMID: 22978849 Free PMC article.
Regulating the ubiquitin/proteasome pathway via cAMP-signaling: neuroprotective potential.
Huang H, Wang H, Figueiredo-Pereira ME. Huang H, et al. Cell Biochem Biophys. 2013 Sep;67(1):55-66. doi: 10.1007/s12013-013-9628-2. Cell Biochem Biophys. 2013. PMID: 23686612 Free PMC article. Review.
Mps1 is associated with the BRAFV600E mutation and predicts poor outcome in patients with colorectal cancer.
Zhang Y, Dong J, Shi R, Feng L, Li Y, Cheng C, Zhang L, Song B, Bi Y, Huang H, Kong P, Guo J, Liu J. Zhang Y, et al. Oncol Lett. 2019 Mar;17(3):2809-2817. doi: 10.3892/ol.2019.9924. Epub 2019 Jan 14. Oncol Lett. 2019. PMID: 30854056 Free PMC article.
NLRP3 Ubiquitination-A New Approach to Target NLRP3 Inflammasome Activation.
Akther M, Haque ME, Park J, Kang TB, Lee KH. Akther M, et al. Int J Mol Sci. 2021 Aug 16;22(16):8780. doi: 10.3390/ijms22168780. Int J Mol Sci. 2021. PMID: 34445484 Free PMC article. Review.

References

1. Behrends C., Harper J.W.. Constructing and decoding unconventional ubiquitin chains. Nature Structural and Molecular Biology. 2011;18:520–528. - PubMed
1. Clague M.J., Urbe S.. Ubiquitin: same molecule, different degradation pathways. Cell. 2010;143:682–685. - PubMed
1. Bedford L.. et al. Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets. Nature Reviews. Drug Discovery. 2011;10:29–46. - PMC - PubMed
1. Eldridge A.G., O'Brien T.. Therapeutic strategies within the ubiquitin proteasome system. Cell Death and Differentiation. 2010;17:4–13. - PubMed
1. Guedat P., Colland F.. Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochemistry. 2007;8(Suppl 1) ), S14. - PMC - PubMed

Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases - PubMed (original) (raw)