Small molecules as tools for functional assessment of deubiquitinating enzyme function
نویسندگان
چکیده
Deubiquitinating enzymes (DUBs) are a largely understudied and untapped resource in the toolkit of protein degradation functionalities. They comprise large repertoire that remove ubiquitin from substrates variety cellular pathophysiological contexts, have enormous potential for research clinical use. It is only within last 5 years potent, selective, well-characterized small-molecule inhibitors DUBs been described. These compounds now being used to study biological roles DUBs. Here, we describe downstream applications studying provide framework future studies. We highlight recent examples using these confirm explore role both normal pathological contexts. studies represent first steps burgeoning field pharmacological chemoproteomic DUBs, which will be critical continued advancement DUB field. Ubiquitination reversible post-translational modification involving covalent attachment substrate (Kerscher et al., 2006Kerscher O. Felberbaum R. Hochstrasser M. Modification proteins by ubiquitin-like proteins.Annu. Rev. Cell Dev. Biol. 2006; 22: 159-180Crossref PubMed Scopus (1204) Google Scholar). The mechanism ubiquitination involves cascade three termed E1, E2, E3, collectively activate C terminus molecule ligate it correct target protein. Substrate can ubiquitinated with single ubiquitin, whereas polyubiquitination consists diverse group architectures; they may linear or branched, constructed through isopeptide bonds between C-terminal glycine one lysine residue (K6, K11, K27, K29, K33, K48, K63) N another (Akutsu 2016Akutsu Dikic I. Bremm A. Ubiquitin chain diversity at glance.J. Sci. 2016; 129: 875-880Crossref (268) Polypeptidic chains also include (Ubls) such as small modifier (SUMO) neuronal precursor cell-expressed developmentally downregulated 8 (NEDD8). To further complicate signaling, Ubls undergo modifications acetylation phosphorylation (Komander Rape, 2012Komander D. Rape code.Annu. 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From discovery bedside: system.Cell Chem. 2018; 26: 156-177Abstract (70) deubiquitinating isopeptidases cleave either itself moieties on polyubiquitin chains. This cleavage cause consequences, rescuing degradation, altering restoring pool free (Figure 1) (Mevissen Komander, 2017Mevissen T.E.T. Komander Mechanisms deubiquitinase specificity regulation.Annu. 2017; 86: 159-192Crossref (446) There seven families total approximately 100 known human DUBs—ubiquitin-specific peptidases (USPs), ovarian tumor proteases (OTUs), Jab1/Mov34/Mpr1 Pad 1 N-terminal + domain (JAMMs), motif interacting ubiquitin-containing novel family (MINDYs), hydroxylases (UCHs), Machado-Josephin (MJDs), zinc finger-containing peptidase (ZUP1). USPs largest family, consisting 56 members, while rest (17 OTUs, 12 JAMMs, handful MJDs, UCHs, MINDYs, ZUP1) other half family. With exception JAMM metalloproteases, cysteine proteases. Each contains ubiquitin-cleaving domain, structurally varies across, even within, subfamilies imparts linkages certain Further structural variation accessory domains contribute addition linkage this diversity, specific different processes pathways, well states. Therefore, development selective window opportunity disease-specific intervention (Schauer 2020bSchauer N.J. Magin R.S. Doherty L.M. Buhrlage S.J. Advances discovering enzyme (DUB) inhibitors.J. 2020; 63: 2731-2750Crossref (57) state inhibitor relatively young, having entered trials, potent recently described characterized, reviewed Some most promising several USP7 (XL188, ALM5, FT671) (Di Lello 2017Di P. Pastor Murray J.M. Blake R.A. Cohen F. Crawford T.D. Drobnick Drummond Kategaya L. Kleinheinz al.Discovery protease 7 (USP7) integrated NMR silico techniques.J. 60: 10056-10070Crossref (35) Gavory 2018Gavory O'Dowd C.R. Helm M.D. Flasz Arkoudis E. Dossang Hughes C. Cassidy McClelland K. 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Finally, directions perspectives rapidly expanding area research. stated above, past seen significant progress hand, uncovered molecules key understanding function their pathophysiology. advantages function, extensively (Arkin Wells, 2004Arkin M.R. Wells J.A. Small-molecule interactions: progressing towards dream.Nat. Drug Discov. 2004; 3: 301-317Crossref (1366) Bedard 2020Bedard P.L. Hyman D.M. Davids M.S. Siu L.L. Small molecules, big impact: 20 targeted therapy oncology.Lancet. 395: 1078-1088Abstract (123) 2009Zhang Yang Gray N.S. Targeting cancer kinase Cancer. 28-39Crossref (1987) minimal impact system, ease flexibility experimental ability easily perform animal models. However, when comes DUB-specific compounds, there suited 2). historically plagued poorly promiscuous systems difficult (Ndubaku Tsui, 2015Ndubaku Tsui Inhibiting (DUBs).J. 2015; 58: 1581-1595Crossref (62) scope functions challenging characterize. particular, conflicting reports substrates, tissue specific. pleiotropic effects knocking out via RNAi CRISPR interpret. Moreover, genetic experiments superphysiological overexpression prone artifactual results whose remains unclear. worth noting activity-based probes (ABPs) tool determining situ selectivity ABPs long involved system. foundational chemical particularly useful target-class approach (Altun 2011Altun Kramer H.B. Willems L.I. McDermott J.L. Leach C.A. Goldenberg Kumar K.G. Konietzny Fischer Kogan al.Activity-based proteomics accelerates deubiquitylating enzymes.Chem. 2011; 18: 1401-1412Abstract (263) powerful tools superfamily few off-targets (notably, DUB-targeting do not label E3 enzymes), purposes (Cravatt 2008Cravatt B.F. 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Many early suffered promiscuity so an stage design help avoiding pitfall later stage. (ABPP) allows determine if changes abrogate against allow gain another. become available, utilized cross-validate existing literature proposed interest. Treatment time courses concentrations precise temporal control then monitor reported cognate phenotypes. Comparing observations correspond interest whether previously detected were on-target re-examination order. unbiased approaches discover candidate functionalities validation (Magin 2020Magin Chapter class.in: Protein Degradation New Chemical Modalities: Successful Strategies Discovery Biology. Royal Society Chemistry), 2020: 234-253Crossref (1) whole-cell transcriptomic upon treatment inhibitor, measure inhibiting and/or proteome examine broader cell. Probes line susceptibility compound, reveal unexpected dependencies pathways. following section, USP7, USP9X, hydrolase L1 (UCHL1), PLpro. rigorously tested off-target effects. such, best follow characterization. HAUSP (herpes virus-associated ubiquitin-specific protease), well-studied (Valles 2020Valles G.J. Bezsonova Woodgate Ashton N.W. master regulator stability.Front. 8: 717Crossref (16) 2019Wang Kang You Pang Ren Suo Zheng USP7: therapy.Front. Pharmacol. 2019; 427Crossref (47) Interest emerged discovered its complex regulating levels suppressor p53 ligase MDM2, responsible ubiquitination. established abrogating causes decrease MDM2 increase along genes, p21. Furthermore, important processes, repair, telomere maintenance, cytosine methylation use knockout overexpress limited due long-term associated perturbation. Several groups (Table 1). Initial hits, P5091, HBX-41108, HBX-19818, shown lack (Reverdy More recently, however, increasingly groups. Three bearing 4-hydroxypiperidine scaffold published 2017 2018 independent groups: XL188, FT671 (Gavory all IC50 values lower nM, panels Work since expanded analog XL177A sub-nanomolar shows extremely high proteome-wide USP7. co-crystallized bind “palm” “thumb” site scaffolds elsewhere reported. 2017, Genentech pair triaryl inhibitors, GNE6640 GNE6776, distinct palm although modest (low micromolar range) Most 2020, 7-pyridylbenzofuran was binds same despite belonging chemotype. lead USP7-797, demonstrated similar 4-hydroxypiperdine (Leger 2020Leger D.X. Biannic Bui Han Karbarz Maung Okano Osipov Shibuya G.M. orally bioavailable vivo antitumor activity.J. 5398-5420Crossref (21) Scholar).Table 1Inhibitors mentioned reviewTargetCompound IDStructureYear reportedReferenceUSP7XL1882017(Lamberto Scholar)FT6712017(Turnbull Scholar)ALM52018(Gavory Ch
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ژورنال
عنوان ژورنال: Cell chemical biology
سال: 2021
ISSN: ['2451-9456', '2451-9448']
DOI: https://doi.org/10.1016/j.chembiol.2021.04.021