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• W2904001172 abstract "The ubiquitin/proteasome system is a primary conduit for selective intracellular protein degradation. Since its discovery over 30 years ago, this highly regulated system continues to be an active research area for drug discovery that is exemplified by several approved drugs. Here we review compounds in preclinical testing, clinical trials, and approved drugs, with the aim of highlighting innovative discoveries and breakthrough therapies that target the ubiquitin system. The ubiquitin/proteasome system is a primary conduit for selective intracellular protein degradation. Since its discovery over 30 years ago, this highly regulated system continues to be an active research area for drug discovery that is exemplified by several approved drugs. Here we review compounds in preclinical testing, clinical trials, and approved drugs, with the aim of highlighting innovative discoveries and breakthrough therapies that target the ubiquitin system. The ubiquitin/proteasome system (UPS) selectively targets proteins for intracellular degradation. Consequently, the UPS modulates essential cellular processes including the cell cycle, gene expression, and responses to growth factors and cellular stress (Finley et al., 2004Finley D. Ciechanover A. Varshavsky A. Ubiquitin as a central cellular regulator.Cell. 2004; S116: S29-S32Abstract Full Text PDF Google Scholar, Herrmann et al., 2007Herrmann J. Lerman L.O. Lerman A. Ubiquitin and ubiquitin-like proteins in protein regulation.Circ. Res. 2007; 100: 1276-1291Crossref PubMed Scopus (193) Google Scholar). This highly regulated machinery directs three major processes: ubiquitylation, deubiquitylation, and proteasomal degradation (Figure 1). Protein ubiquitylation is orchestrated by three classes of enzymes. First, upon binding to both ubiquitin and ATP-Mg2+, E1 enzymes (ubiquitin-activating enzymes) catalyze the formation of ubiquitin-AMP complex through ubiquitin C-terminal acyl adenylation (Schulman and Harper, 2009Schulman B.A. Harper J.W. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways.Nat. Rev. Mol. Cell Biol. 2009; 10: 319-331Crossref PubMed Scopus (377) Google Scholar). Next a catalytic cysteine on the E1 replaces the AMP group in the ubiquitin-AMP complex, forming an activated ubiquitin through a covalent thioester bond. E1-ubiquitin complexes then transfer ubiquitin to E2 enzymes (ubiquitin-conjugating enzyme) via a transthioesterification reaction (Ye and Rape, 2009Ye Y. Rape M. Building ubiquitin chains: E2 enzymes at work.Nat. Rev. Mol. Cell Biol. 2009; 10: 755-764Crossref PubMed Scopus (474) Google Scholar). E3s (ubiquitin ligases) then interact with both the E2-ubiquitin complex and a substrate protein to catalyze the covalent transfer of ubiquitin, by forming an amide bond most commonly with a Lys residue or the N terminus of the substrate (Buetow and Huang, 2016Buetow L. Huang D.T. Structural insights into the catalysis and regulation of E3 ubiquitin ligases.Nat. Rev. Mol. Cell Biol. 2016; 17: 626-642Crossref PubMed Google Scholar), although reports of non-Lys residue ubiquitylation are emerging (Kravtsova-Ivantsiv and Ciechanover, 2012Kravtsova-Ivantsiv Y. Ciechanover A. Non-canonical ubiquitin-based signals for proteasomal degradation.J. Cell. Sci. 2012; 125: 539-548Crossref PubMed Scopus (117) Google Scholar, Pao et al., 2018Pao K.-C. Wood N.T. Knebel A. Rafie K. Stanley M. Mabbitt P.D. Sundaramoorthy R. Hofmann K. van Aalten D.M.F. Virdee S. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity.Nature. 2018; 556: 381-385Crossref PubMed Scopus (0) Google Scholar). The same cycle may be repeated to result in substrate multi-monoubiquitylation, or the formation of polyubiquitin chains. In some cases, polyubiquitylation requires ubiquitin-chain elongation factors, referred to as E4 enzymes (Hoppe, 2005Hoppe T. Multiubiquitylation by E4 enzymes: 'one size' doesn’t fit all.Trends Biochem. Sci. 2005; 30: 183-187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Ubiquitin modifications direct the fate of the substrates. The functions of ubiquitin modifications are dictated by their distinct structural topologies, which in turn are recognized by specific cellular ubiquitin receptors. In this review, we focus on the proteasome-targeting functions of ubiquitin modifications. These are achieved by Lys-11- and Lys-48-linked polyubiquitin chains, although other types of ubiquitin modifications may also direct degradation by the proteasome (Yau and Rape, 2016Yau R. Rape M. The increasing complexity of the ubiquitin code.Nat. Cell Biol. 2016; 18: 579-586Crossref PubMed Google Scholar). The human proteasome is an approximately 2.5-MDa complex composed of at least 33 different subunits that can be generally divided into two components: (1) regulatory particles such as the 19S lid, PA28, or PA200, that contain ATPases, ubiquitin receptors, and deubiquitinases; and (2) the core particle (20S) that contains the proteolytic enzymes. The β1, β2, or β5 proteasome core protease subunits have caspase-like, tryptic-like, or chymotryptic-like activities, respectively, and thus proteolyze a wide range of substrates (Yu and Matouschek, 2017Yu H. Matouschek A. Recognition of client proteins by the proteasome.Annu. Rev. Biophys. 2017; 46: 149-173Crossref PubMed Scopus (10) Google Scholar). Given the importance of ubiquitin modifications in regulating essential cellular processes, it is essential that ubiquitylation can be reversed. This is achieved by deubiquitinase enzymes (DUBs), of which approximately 100 members are encoded by the human genome. Seven DUB families have been identified including USP, UCH, OTU, Josephin, MINDY, and ZUFSP/ZUP families that are Cys proteases, as well as the JAMM deubiquitinases that are metalloproteases (Coleman and Huang, 2018Coleman K.E. Huang T.T. In a class of its own: a new family of deubiquitinases promotes genome stability.Mol. Cell. 2018; 70: 1-3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Mevissen and Komander, 2017Mevissen T.E.T. Komander D. Mechanisms of deubiquitinase specificity and regulation.Annu. Rev. Biochem. 2017; 86: 159-192Crossref PubMed Scopus (58) Google Scholar). Cys deubiquitinases rely on the nucleophilic attack of the catalytic Cys on the amide bond to form a thiol acyl intermediate, which then reacts with water to fully hydrolyze the amide bond and remove the ubiquitin moiety. JAMM deubiquitinases are zinc-dependent metalloproteases. Amide bond hydrolysis by JAMM proteases is achieved by a concerted mechanism with water in the active site attacking the amide bond while zinc and other catalytic residues coordinate and thus lower the hydrolysis activation energy. Since recognition by the 2004 Nobel Prize, discoveries in the UPS field continue to offer new insights. Much effort has been focused on developing small molecules to modulate this pathway for therapeutic benefit. In this review we summarize recent literature focusing on small-molecule inhibitors of enzymes that promote substrate ubiquitylation, deubiquitinase inhibitors, and inhibitors of proteasome function. We direct our readers to review articles that summarize more historical compounds (e.g., Brown and Mark, 2014Brown J. Mark J. Targeted chemical libraries: the keys to unlock the ubiquitin system.Drug Discov. World. 2014; : 66-74Google Scholar, Guédat and Colland, 2007Guédat P. Colland F. Patented small molecule inhibitors in the ubiquitin proteasome system.BMC Biochem. 2007; 8: S14Crossref PubMed Scopus (0) Google Scholar, Huang and Dixit, 2016Huang X. Dixit V.M. Drugging the undruggables: exploring the ubiquitin system for drug development.Cell Res. 2016; 26: 484-498Crossref PubMed Scopus (113) Google Scholar, Lill and Wertz, 2014Lill J.R. Wertz I.E. Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics.Trends Pharmacol. Sci. 2014; 35: 187-207Abstract Full Text Full Text PDF PubMed Google Scholar, Mattern et al., 2012Mattern M.R. Wu J. Nicholson B. Ubiquitin-based anticancer therapy: carpet bombing with proteasome inhibitors vs surgical strikes with E1, E2, E3, or DUB inhibitors.Biochim. Biophys. Acta. 2012; 1823: 2014-2021Crossref PubMed Scopus (0) Google Scholar, Micel et al., 2013Micel L.N. Tentler J.J. Smith P.G. Eckhardt G.S. Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies.J. Clin. Oncol. 2013; 31: 1231-1238Crossref PubMed Scopus (0) Google Scholar). We focus on compounds in preclinical testing, in clinical trials, and Food and Drug Administration (FDA)-approved therapeutics in order to exemplify translatability from basic research to clinical efficacy. The human proteome contains 2 E1, approximately 40 E2, and over 600 E3 enzymes. Substrate specificity of E3 is high compared with E1 and E2 enzymes, which may translate into better safety windows. Nevertheless, challenges exist in targeting E3s due to the lack of apparent druggable sites. With the development of new screening technologies, our abilities to drug challenging targets will likely improve. The E1-E2-E3 enzymatic cascade of ubiquitin conjugation was first dissected in the 1980s (Finley et al., 2004Finley D. Ciechanover A. Varshavsky A. Ubiquitin as a central cellular regulator.Cell. 2004; S116: S29-S32Abstract Full Text PDF Google Scholar, Hershko et al., 1983Hershko A. Heller H. Elias S. Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown.J. Biol. Chem. 1983; 258: 8206-8214Abstract Full Text PDF PubMed Google Scholar). More than two decades later, the first cell permeable E1 inhibitor, PYR-41 (Table 1), was identified (Yang et al., 2007Yang Y. Kitagaki J. Dai R.-M. Tsai Y.C. Lorick K.L. Ludwig R.L. Pierre S.A. Jensen J.P. Davydov I.V. Oberoi P. et al.Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics.Cancer Res. 2007; 67: 9472-9481Crossref PubMed Scopus (249) Google Scholar). A high-throughput screening (HTS) for inhibitors of the Hdm2 E3 identified PYR-41, which inhibited E1 but not E2 or caspase proteases by forming a covalent bond selectively with the cysteine group of E1. PYR-41 also partially inhibits auto-ubiquitylation of HECT E3 ligases, namely Nedd4 and E6-AP in vitro, albeit to a lesser extent than E1. PYR-41 also attenuated cytokine-mediated nuclear factor κB activation and activated p53 transcriptional activity. In subsequent studies, PYR-41 attenuated angiotensin II-induced activation of dendritic cells (Chen et al., 2014Chen C. Meng Y. Wang L. Wang H.-X. Tian C. Pang G.-D. Li H.-H. Du J. Ubiquitin-activating enzyme E1 inhibitor PYR41 attenuates angiotensin II-induced activation of dendritic cells via the IκBa/NF-κB and MKP1/ERK/STAT1 pathways.Immunology. 2014; 142: 307-319Crossref PubMed Scopus (12) Google Scholar) and lung injury in sepsis (Matsuo et al., 2018Matsuo S. Sharma A. Wang P. Yang W.-L. PYR-41, a ubiquitin-activating enzyme E1 inhibitor, attenuates lung injury in sepsis.Shock. 2018; 49: 442-450Crossref PubMed Scopus (4) Google Scholar).Table 1Recently Reported E1, E2, E3, DUB, or Proteasome Modulators in Preclinical TestingCompoundTargetMOAaMechanism of action (MOA).BMRB or PDBbBiological Magnetic Resonance Bank (BMRB) or Protein Data Bank (PDB).Refs.E1 Enzyme ModulatorsPYR-41Uba1irreversible inhibition of ubiquitin activation by reacting with a cysteine group in E1noYang et al., 2007Yang Y. Kitagaki J. Dai R.-M. Tsai Y.C. Lorick K.L. Ludwig R.L. Pierre S.A. Jensen J.P. Davydov I.V. Oberoi P. et al.Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics.Cancer Res. 2007; 67: 9472-9481Crossref PubMed Scopus (249) Google ScholarADS (Takeda)Uba5reacting with Uba5∼Ufm1 thioester and forming a covalent bond with Ufm1noGavin et al., 2014Gavin J.M. Hoar K. Xu Q. Ma J. Lin Y. Chen J. Chen W. Bruzzese F.J. Harrison S. Mallender W.D. et al.Mechanistic study of Uba5 enzyme and the Ufm1 conjugation pathway.J. Biol. Chem. 2014; 289: 22648-22658Crossref PubMed Scopus (8) Google Scholar8.5Uba5exact MOA unknownnoda Silva et al., 2016da Silva S.R. Paiva S.-L. Bancerz M. Geletu M. Lewis A.M. Chen J. Cai Y. Lukkarila J.L. Li H. Gunning P.T. A selective inhibitor of the UFM1-activating enzyme, UBA5.Bioorg. Med. Chem. Lett. 2016; 26: 4542-4547Crossref PubMed Scopus (4) Google ScholarE2 Enzyme ModulatorsCC0651Ube2R1 hCdc34inhibiting ubiquitin transfer to substrate by allosteric binding to hCdc34PDB: 3RZ3Ceccarelli et al., 2011Ceccarelli D.F. Tang X. Pelletier B. Orlicky S. Xie W. Plantevin V. Neculai D. Chou Y.-C. Ogunjimi A. Al-Hakim A. et al.An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme.Cell. 2011; 145: 1075-1087Abstract Full Text Full Text PDF PubMed Scopus (108) Google ScholarNSC697923Ubc13forming covalent adduct with Ubc13 active-site cysteinePDB: 4ONMHodge et al., 2015Hodge C.D. Edwards R.A. Markin C.J. McDonald D. Pulvino M. Huen M.S.Y. Zhao J. Spyracopoulos L. Hendzel M.J. Glover J.N.M. Covalent inhibition of Ubc13 affects ubiquitin signaling and reveals active site elements important for targeting.ACS Chem. Biol. 2015; 10: 1718-1728Crossref PubMed Scopus (16) Google Scholar6dUbcH5cinactivating UbcH5c irreversiblynoneChen et al., 2017aChen H. Wu G. Gao S. Guo R. Zhao Z. Yuan H. Liu S. Wu J. Lu X. Yuan X. et al.Discovery of potent small-molecule inhibitors of ubiquitin-conjugating enzyme UbcH5c from α-santonin derivatives.J. Med. Chem. 2017; 60: 6828-6852Crossref PubMed Scopus (2) Google ScholarE3 ModulatorsAuxinSCFTIR1promoting SCF ubiquitin-ligase-catalyzed degradation of AUX/IAA transcription repressorsPDB: 2P1M, 2P1P, 2P1QTan et al., 2007Tan X. Calderon-Villalobos L.I.A. Sharon M. Zheng C. Robinson C.V. Estelle M. Zheng N. Mechanism of auxin perception by the TIR1 ubiquitin ligase.Nature. 2007; 446: 640-645Crossref PubMed Scopus (800) Google ScholarBI-0252 (BI)MDM2:p53inhibiting MDM2:p53 protein-protein interaction by antagonizing p53 binding to MDM2PDB: 5LAZGollner et al., 2016Gollner A. Rudolph D. Arnhof H. Bauer M. Blake S.M. Boehmelt G. Cockroft X.-L. Dahmann G. Ettmayer P. Gerstberger T. et al.Discovery of novel spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds as chemically stable and orally active inhibitors of the MDM2-p53 interaction.J. Med. Chem. 2016; 59: 10147-10162Crossref PubMed Scopus (13) Google Scholar17 (BMS)XIAP and cIAPinducing proteasome degradation of cIAP and disrupting XIAP interaction with caspasesnonePerez et al., 2015Perez H.L. Chaudhry C. Emanuel S.L. Fanslau C. Fargnoli J. Gan J. Kim K.S. Lei M. Naglich J.G. Traeger S.C. et al.Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity.J. Med. Chem. 2015; 58: 1556-1562Crossref PubMed Scopus (8) Google Scholar21 (Astex)XIAP and cIAPinducing proteasome degradation of cIAP and disrupting XIAP interaction with caspasesPDB: 5C83Chessari et al., 2015Chessari G. Buck I.M. Day J.E.H. Day P.J. Iqbal A. Johnson C.N. Lewis E.J. Martins V. Miller D. Reader M. et al.Fragment-based drug discovery targeting inhibitor of apoptosis proteins: discovery of a non-alanine lead series with dual activity against cIAP1 and XIAP.J. Med. Chem. 2015; 58: 6574-6588Crossref PubMed Scopus (24) Google ScholarAT-IAP (Astex)XIAP and cIAPinducing proteasome degradation of cIAP and disrupting XIAP interaction with caspasesPDB: 5M6L, 5M6NTamanini et al., 2017Tamanini E. Buck I.M. Chessari G. Chiarparin E. Day J.E.H. Frederickson M. Griffiths-Jones C.M. Hearn K. Heightman T.D. Iqbal A. et al.Discovery of a potent nonpeptidomimetic, small-molecule antagonist of cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP).J. Med. Chem. 2017; 60: 4611-4625Crossref PubMed Scopus (4) Google ScholarVH298VHLbinding to VHL and disrupting VHL:HIF-α PPIPDB: 5LLIFrost et al., 2016Frost J. Galdeano C. Soares P. Gadd M.S. Grzes K.M. Ellis L. Epemolu O. Shimamura S. Bantscheff M. Grandi P. et al.Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.Nat. Commun. 2016; 7: 13312Crossref PubMed Scopus (28) Google Scholar, Soares et al., 2017Soares P. 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A small molecule that switches a ubiquitin ligase from a processive to a distributive enzymatic mechanism.J. Am. Chem. Soc. 2015; 137: 12442-12445Crossref PubMed Scopus (12) Google ScholarDeneddylase InhibitorCSN5i-3CSN5CSN5 inhibition traps CRLs in the neddylated state, which leads to the inactivation of CRLs by inducing the auto-ubiquitylation and degradation of substrate recognition modulesPDB: 5JOGSchlierf et al., 2016Schlierf A. Altmann E. Quancard J. Jefferson A.B. Assenberg R. Renatus M. Jones M. Hassiepen U. Schaefer M. Kiffe M. et al.Targeted inhibition of the COP9 signalosome for treatment of cancer.Nat. Commun. 2016; 7: 13166Crossref PubMed Scopus (24) Google ScholarDeubiquitinase InhibitorsML364USP2, USP8inhibits USP2 and USP8 activity. Reduces cyclin D1 protein levels to induce G0/G1 cell-cycle arrest and decrease cell proliferationnoneDavis et al., 2016Davis M.I. Pragani R. Fox J.T. Shen M. Parmar K. Gaudiano E.F. Liu L. Tanega C. McGee L. Hall M.D. et al.Small molecule inhibition of the ubiquitin-specific protease USP2 accelerates cyclin D1 degradation and leads to cell cycle arrest in colorectal cancer and mantle cell lymphoma models.J. Biol. Chem. 2016; 291: 24628-24640Crossref PubMed Scopus (18) Google ScholarLCAHAUSP2 and other DUBsinhibits USP2 and other DUBs in an in vitro DUB selectivity panel. Reduces cyclin D1, aurora-A, and cyclin-A protein levels to decrease cell proliferationnoneMagiera et al., 2017Magiera K. Tomala M. Kubica K. De Cesare V. Trost M. Zieba B.J. Kachamakova-Trojanowska N. Les M. Dubin G. Holak T.A. et al.Lithocholic acid hydroxyamide destabilizes cyclin D1 and induces G0/G1 arrest by inhibiting deubiquitinase USP2a.Cell Chem. Biol. 2017; 24: 458-470.e18Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar6TGUSP2, other DUBs not testedpossible covalent bonding interaction between 6TG and the USP2 catalytic Cys276 residue. Cellular MOA not evaluatedPDB: 5XU8, 5XVEChuang et al., 2018Chuang S.-J. Cheng S.-C. Tang H.-C. Sun C.-Y. Chou C.-Y. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2.Sci. Rep. 2018; 8: 3102Crossref PubMed Scopus (1) Google ScholarHBX19818USP7 and other DUBsforms a covalent bond with USP7 catalytic Cys223noneReverdy et al., 2012Reverdy C. Conrath S. Lopez R. Planquette C. Atmanene C. Collura V. Harpon J. Battaglia V. Vivat V. Sippl W. et al.Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme.Chem. Biol. 2012; 19: 467-477Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, Weisberg et al., 2017Weisberg E.L. Schauer N.J. Yang J. Lamberto I. Doherty L. Bhatt S. Nonami A. Meng C. Letai A. Wright R. et al.Inhibition of USP10 induces degradation of oncogenic FLT3.Nat. Chem. Biol. 2017; 13: 1207-1215Crossref PubMed Scopus (0) Google ScholarP22077USP7, USP47covalently and irreversibly modifies the USP7 catalytic C223 residueBMRB: 26951Pozhidaeva et al., 2017Pozhidaeva A. Valles G. Wang F. Wu J. Sterner D.E. Nguyen P. Weinstock J. Kumar K.G.S. Kanyo J. Wright D. et al.USP7-specific inhibitors target and modify the enzyme's active site via distinct chemical mechanisms.Cell Chem. Biol. 2017; 24: 1501-1512.e5Abstract Full Text Full Text PDF PubMed Scopus (5) Google ScholarP50429USP7, USP47covalently and irreversibly modifies the USP7 catalytic C223 residueBMRB: 26951Pozhidaeva et al., 2017Pozhidaeva A. Valles G. Wang F. Wu J. Sterner D.E. Nguyen P. Weinstock J. Kumar K.G.S. Kanyo J. Wright D. et al.USP7-specific inhibitors target and modify the enzyme's active site via distinct chemical mechanisms.Cell Chem. Biol. 2017; 24: 1501-1512.e5Abstract Full Text Full Text PDF PubMed Scopus (5) Google ScholarXL188USP7non-covalently binds and inhibits the USP7 active site. The enantiomer XL203C is 80-fold less potentPDB: 5VS6Lamberto et al., 2017Lamberto I. Liu X. Seo H.-S. Schauer N.J. Iacob R.E. Hu W. Das D. Mikhailova T. Weisberg E.L. Engen J.R. et al.Structure-guided development of a potent and selective non-covalent active-site inhibitor of USP7.Cell Chem. Biol. 2017; 24: 1490-1500.e11Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar4: R = (R)-Me6: R = (S)-MeUSP7non-covalently binds and inhibits the USP7 active site. The enantiomer is 400-fold less potentPDB: 5N9R, 5N9TGavory et al., 2018Gavory G. O'Dowd C.R. Helm M.D. Flasz J. Arkoudis E. Dossang A. Hughes C. Cassidy E. McClelland K. Odrzywol E. et al.Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.Nat. Chem. 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Cohen F. Crawford T.D. Drobnick J. Drummond J. Kategaya L. et al.Discovery of small-molecule inhibitors of ubiquitin specific protease 7 (USP7) using integrated NMR and in silico techniques.J. Med. Chem. 2017; 60: 10056-10070Crossref PubMed Scopus (5) Google Scholar, Kategaya et al., 2017Kategaya L. Di Lello P. Rougé L. Pastor R. Clark K.R. Drummond J. Kleinheinz T. Lin E. Upton J.-P. Prakash S. et al.USP7 small-molecule inhibitors interfere with ubiquitin binding.Nature. 2017; 550: 534-538Crossref PubMed Scopus (28) Google ScholarGNE-6776binds 12 Å distant from the USP7 catalytic triad to attenuate binding of ubiquitin-K48 with USP7-D305/E308PDB: 5UQXBMRB: 267663USP10, USP7an HBX19818 analog more potent for USP10 than HBX19818noneWeisberg et al., 2017Weisberg E.L. Schauer N.J. Yang J. Lamberto I. Doherty L. Bhatt S. Nonami A. Meng C. Letai A. Wright R. et al.Inhibition of USP10 induces degradation of oncogenic FLT3.Nat. Chem. Biol. 2017; 13: 1207-1215Crossref PubMed Scopus (0) Google Scholar9USP10, other DUBs not testedan HBX19818 analog more selective for USP10 over USP7EOAI3402143(G9)USP9X, USP24, USP5 and other DUBsa derivative of WP1130 that inhibits USP9X and other cellular DUBs. Decreases Mcl-1 and other oncoproteins to promote cell deathnonePal et al., 2018Pal A. Dziubinski M. Di Magliano M.P. Simeone D.M. Owens S. Thomas D. Peterson L. Potu H. Talpaz M. Donato N.J. usp9x promotes survival in human pancreatic cancer and its inhibition suppresses pancreatic ductal adenocarcinoma in vivo tumor growth.Neoplasia. 2018; 20: 152-164Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Peterson et al., 2015Peterson L.F. Sun H. Liu Y. Potu H. Kandarpa M. Ermann M. Courtney S.M. Young M. Showalter H.D. 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• W2904001172 created "2018-12-22" @default.
• W2904001172 creator A5058060903 @default.
• W2904001172 creator A5083134393 @default.
• W2904001172 date "2019-02-01" @default.
• W2904001172 modified "2023-10-12" @default.
• W2904001172 title "From Discovery to Bedside: Targeting the Ubiquitin System" @default.
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