Abstract
Ubiquitination is a key regulatory mechanism vital for maintenance of cellular homeostasis. Protein degradation is induced by E3 ligases via attachment of ubiquitin chains to substrates. Pharmacological exploitation of this phenomenon via targeted protein degradation (TPD) can be achieved with molecular glues or bifunctional molecules facilitating the formation of ternary complexes between an E3 ligase and a given protein of interest (POI), resulting in ubiquitination of the substrate and subsequent proteolysis by the proteasome. Recently, the development of novel covalent fragment screening approaches has enabled the identification of first-in-class ligands for E3 ligases and deubiquitinases revealing so far unexplored binding sites which highlights the potential of these methods to uncover and expand druggable space for new target classes.
About the authors
Elisabeth M. Rothweiler completed her degree in Pharmacy at the Ludwig-Maximilians-Universität (LMU) Munich in 2018. In October 2019 she started her research project as a Nuffield Department of Medicine studentship DPhil candidate. Currently, she is investigating novel approaches for targeted protein degradation and ligand-based screening.
Prof. Paul E. Brennan received his PhD in organic chemistry from UC Berkeley working on combinatorial chemistry and antibiotics. Following post-doctoral research in Cambridge University on total synthesis, Paul returned to California to take a position at Amgen. His research was focused on kinase inhibitors for oncology. After two years at Amgen, Paul moved to Pfizer in Sandwich, UK and, in 2011, Paul joined the Structural Genomics Consortium as Professor of Medicinal Chemistry to discover chemical probes for epigenetic proteins. Over the course of his career, Paul has worked on most major drug classes of drug targets: kinases, GPCR’s, CNS-targets, ion-channels, metabolic enzymes, and epigenetic readers, writers and erasers. Paul is currently Professor of Medicinal Chemistry and Chief Scientific Officer of the Alzheimer’s Research UK Oxford Drug Discovery Institute in the Centre for Medicines Discovery at the University of Oxford. His research is focused on finding new treatments for dementia and discovering chemical probes for novel protein families.
Dr. Kilian V. M. Huber received his doctorate in Medicinal and Pharmaceutical Chemistry from the Ludwig-Maximilians-Universität (LMU) in Munich working on the design and synthesis of natural product-inspired kinase inhibitors in the group Prof Franz Bracher. After postdoctoral studies at the Department of Chemistry, University of Oxford, and at the Research Centre for Molecular Medicine (CeMM), Vienna, he joined the Nuffield Department of Medicine at Oxford in 2015 as Principal Investigator and Chemical Biology Group Leader.
Acknowledgments
The authors would like to thank Dr. Philipp Cromm and Dr. Volker Badock for helpful discussions as well as Dr. Andrew Lewis and all members of the Huber research group for critical reading of this manuscript. EMR and KVMH are grateful for support from Bayer AG.
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan, Diamond Light Source Limited.
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
Abo, M., Bak, D.W., and Weerapana, E. (2017). Optimization of caged electrophiles for improved monitoring of cysteine reactivity in living cells. Chembiochem 18: 81–84, https://doi.org/10.1002/cbic.201600524.Search in Google Scholar PubMed PubMed Central
Abo, M. and Weerapana, E. (2015). A caged electrophilic probe for global analysis of cysteine reactivity in living cells. J. Am. Chem. Soc. 137: 7087–7090, https://doi.org/10.1021/jacs.5b04350.Search in Google Scholar PubMed
Aljoundi, A., Bjij, I., El Rashedy, A., and Soliman, M.E.S. (2020). Covalent versus non-covalent enzyme inhibition: which route should we take? A justification of the good and bad from molecular modelling perspective. Protein J. 39: 97–105, https://doi.org/10.1007/s10930-020-09884-2.Search in Google Scholar PubMed
Backus, K.M., Correia, B.E., Lum, K.M., Forli, S., Horning, B.D., Gonzalez-Paez, G.E., Chatterjee, S., Lanning, B.R., Teijaro, J.R., Olson, A.J., et al.. (2016). Proteome-wide covalent ligand discovery in native biological systems. Nature 534: 570–574, https://doi.org/10.1038/nature18002.Search in Google Scholar PubMed PubMed Central
Baek, K. and Schulman, B.A. (2020). Molecular glue concept solidifies. Nat. Chem. Biol. 16: 2–3, https://doi.org/10.1038/s41589-019-0414-3.Search in Google Scholar PubMed
Bar-Peled, L., Kemper, E.K., Suciu, R.M., Vinogradova, E.V., Backus, K.M., Horning, B.D., Paul, T.A., Ichu, T.A., Svensson, R.U., Olucha, J., et al.. (2017). Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171: 696–709, e623, https://doi.org/10.1016/j.cell.2017.08.051.Search in Google Scholar PubMed PubMed Central
Belcher, B.P., Ward, C.C., and Nomura, D.K. (2021). Ligandability of E3 ligases for targeted protein degradation applications. Biochemistry, https://doi.org/10.1021/acs.biochem.1c00464.Search in Google Scholar PubMed PubMed Central
Blewett, M.M., Xie, J., Zaro, B.W., Backus, K.M., Altmann, A., Teijaro, J.R., and Cravatt, B.F. (2016). Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10, https://doi.org/10.1126/scisignal.aaf7694.Search in Google Scholar PubMed PubMed Central
Boike, L., Cioffi, A.G., Majewski, F.C., Co, J., Henning, N.J., Jones, M.D., Liu, G., McKenna, J.M., Tallarico, J.A., Schirle, M., et al.. (2020). Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chem Biol. 28: 4–13, e17, https://doi.org/10.1016/j.chembiol.2020.09.001.Search in Google Scholar PubMed PubMed Central
Bondeson, D.P., Smith, B.E., Burslem, G.M., Buhimschi, A.D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B.D., Ishchenko, A., and Crews, C.M. (2018). Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol. 25: 78–87, e75, https://doi.org/10.1016/j.chembiol.2017.09.010.Search in Google Scholar PubMed PubMed Central
Buckley, D.L., Gustafson, J.L., Van Molle, I., Roth, A.G., Tae, H.S., Gareiss, P.C., Jorgensen, W.L., Ciulli, A., and Crews, C.M. (2012). Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. Angew. Chem. Int. Ed. 51: 11463–11467, https://doi.org/10.1002/anie.201206231.Search in Google Scholar PubMed PubMed Central
Bussiere, D.E., Xie, L., Srinivas, H., Shu, W., Burke, A., Be, C., Zhao, J., Godbole, A., King, D., Karki, R.G., et al.. (2020). Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 16: 15–23, https://doi.org/10.1038/s41589-019-0411-6.Search in Google Scholar PubMed
Chen, X., Wong, Y.K., Wang, J., Zhang, J., Lee, Y.M., Shen, H.M., Lin, Q., and Hua, Z.C. (2017). Target identification with quantitative activity based protein profiling (ABPP). Proteomics 17: 3–4, https://doi.org/10.1002/pmic.201600212.Search in Google Scholar PubMed
Chung, C.Y.-S., Shin, H.R., Berdan, C.A., Ford, B., Ward, C.C., Olzmann, J.A., Zoncu, R., and Nomura, D.K. (2019). Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nat. Chem. Biol. 15: 776–785, https://doi.org/10.1038/s41589-019-0308-4.Search in Google Scholar PubMed PubMed Central
Coleman, K.G. and Crews, C.M. (2018). Proteolysis-targeting chimeras: harnessing the ubiquitin-proteasome system to induce degradation of specific target proteins. 2: 41–58, https://doi.org/10.1146/annurev-cancerbio-030617-050430.Search in Google Scholar
Couvertier, S.M. and Weerapana, E. (2014). Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold. Med. Chem. Commun. 5: 358–362, https://doi.org/10.1039/c3md00289f.Search in Google Scholar
Cravatt, B.F., Wright, A.T., and Kozarich, J.W. (2008). Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem. 77: 383–414, https://doi.org/10.1146/annurev.biochem.75.101304.124125.Search in Google Scholar PubMed
Crowley, V.M., Thielert, M., and Cravatt, B.F. (2021). Functionalized scout fragments for site-specific covalent ligand discovery and optimization. ACS Cent. Sci. 4: 613–623. https://doi.org/10.1021/acscentsci.0c01336.Search in Google Scholar PubMed PubMed Central
Deshaies, R.J. and Joazeiro, C.A. (2009). RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78: 399–434, https://doi.org/10.1146/annurev.biochem.78.101807.093809.Search in Google Scholar PubMed
Doak, B.C., Norton, R.S., and Scanlon, M.J. (2016). The ways and means of fragment-based drug design. Pharmacol. Ther. 167: 28–37, https://doi.org/10.1016/j.pharmthera.2016.07.003.Search in Google Scholar PubMed
Du, X., Volkov, O.A., Czerwinski, R.M., Tan, H., Huerta, C., Morton, E.R., Rizzi, J.P., Wehn, P.M., Xu, R., Nijhawan, D., et al.. (2019). Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27: 1625–1633, e1623, https://doi.org/10.1016/j.str.2019.10.005.Search in Google Scholar PubMed
Ekkebus, R., van Kasteren, S.I., Kulathu, Y., Scholten, A., Berlin, I., Geurink, P.P., de Jong, A., Goerdayal, S., Neefjes, J., Heck, A.J., et al.. (2013). On terminal alkynes that can react with active-site cysteine nucleophiles in proteases. J. Am. Chem. Soc. 135: 2867–2870, https://doi.org/10.1021/ja309802n.Search in Google Scholar PubMed PubMed Central
Faust, T.B., Yoon, H., Nowak, R.P., Donovan, K.A., Li, Z., Cai, Q., Eleuteri, N.A., Zhang, T., Gray, N.S., and Fischer, E.S. (2019). Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16: 7–14, https://doi.org/10.1038/s41589-019-0378-3.Search in Google Scholar PubMed PubMed Central
Gehringer, M. and Laufer, S.A. (2019). Emerging and re-emerging warheads for targeted covalent inhibitors: applications in medicinal chemistry and chemical biology. J. Med. Chem. 62: 5673–5724, https://doi.org/10.1021/acs.jmedchem.8b01153.Search in Google Scholar PubMed
Grams, R.J. and Hsu, K.-L. (2022). Reactive chemistry for covalent probe and therapeutic development. Trends Pharmacol. Sci. 3: 249–262. https://doi.org/10.1016/j.tips.2021.12.002.Search in Google Scholar PubMed PubMed Central
Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., Di Lello, P., Fry, D., Garvie, C., Huang, K.S., et al.. (2012). Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc. Natl. Acad. Sci. U.S.A. 109: 11788–11793, https://doi.org/10.1073/pnas.1203789109.Search in Google Scholar PubMed PubMed Central
Greenbaum, D., Baruch, A., Hayrapetian, L., Darula, Z., Burlingame, A., Medzihradszky, K.F., and Bogyo, M. (2002). Chemical approaches for functionally probing the proteome. Mol. Cell. Proteomics 1: 60–68, https://doi.org/10.1074/mcp.t100003-mcp200.Search in Google Scholar PubMed
Han, T., Goralski, M., Gaskill, N., Capota, E., Kim, J., Ting, T.C., Xie, Y., Williams, N.S., and Nijhawan, D. (2017). Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356: eaal3755, https://doi.org/10.1126/science.aan7977.Search in Google Scholar PubMed
Harrigan, J.A., Jacq, X., Martin, N.M., and Jackson, S.P. (2018). Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat. Rev. Drug Discov. 17: 57–78, https://doi.org/10.1038/nrd.2017.152.Search in Google Scholar PubMed PubMed Central
Hein, J.E. and Fokin, V.V. (2010). Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides. Chem. Soc. Rev. 39: 1302–1315, https://doi.org/10.1039/b904091a.Search in Google Scholar PubMed PubMed Central
Henning, N.J., Boike, L., Spradlin, J.N., Ward, C.C., Belcher, B., Brittain, S.M., Hesse, M., Dovala, D., McGregor, L.M., McKenna, J.M., et al.. (2021). Deubiquitinase-targeting chimeras for targeted protein stabilization. bioRxiv.10.1038/s41589-022-00971-2Search in Google Scholar PubMed
Henning, N.J., Manford, A.G., Spradlin, J.N., Brittain, S.M., Zhang, E., McKenna, J.M., Tallarico, J.A., Schirle, M., Rape, M., and Nomura, D.K. (2022). Discovery of a covalent FEM1B recruiter for targeted protein degradation applications. J. Am. Chem. Soc. 2: 701–708. https://doi.org/10.1021/jacs.1c03980.Search in Google Scholar PubMed PubMed Central
Hoch, D.G., Abegg, D., and Adibekian, A. (2018). Cysteine-reactive probes and their use in chemical proteomics. Chem. Commun. (Cambr) 54: 4501–4512, https://doi.org/10.1039/c8cc01485j.Search in Google Scholar PubMed
Hopkins, A.L. and Groom, C.R. (2002). The druggable genome. Nat. Rev. Drug Discov. 1: 727–730, https://doi.org/10.1038/nrd892.Search in Google Scholar PubMed
Isobe, Y., Okumura, M., McGregor, L.M., Brittain, S.M., Jones, M.D., Liang, X., White, R., Forrester, W., McKenna, J.M., Tallarico, J.A., et al.. (2020). Manumycin polyketides act as molecular glues between UBR7 and P53. Nat. Chem. Biol. 16: 1189–1198, https://doi.org/10.1038/s41589-020-0557-2.Search in Google Scholar PubMed PubMed Central
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., and Handa, H. (2010). Identification of a primary target of thalidomide teratogenicity. Sci 327: 1345–1350, https://doi.org/10.1126/science.1177319.Search in Google Scholar PubMed
Jackson, P.A., Widen, J.C., Harki, D.A., and Brummond, K.M. (2017). Covalent modifiers: a chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-michael addition reactions. J. Med. Chem. 60: 839–885, https://doi.org/10.1021/acs.jmedchem.6b00788.Search in Google Scholar PubMed PubMed Central
Johansson, H., Isabella Tsai, Y.-C., Fantom, K., Chung, C.-W., Kümper, S., Martino, L., Thomas, D.A., Eberl, H.C., Muelbaier, M., House, D., et al.. (2019). Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP. J. Am. Chem. Soc. 141: 2703–2712, https://doi.org/10.1021/jacs.8b13193.Search in Google Scholar PubMed PubMed Central
Jost, C., Nitsche, C., Scholz, T., Roux, L., and Klein, C.D. (2014). Promiscuity and selectivity in covalent enzyme inhibition: a systematic study of electrophilic fragments. J. Med. Chem. 57: 7590–7599, https://doi.org/10.1021/jm5006918.Search in Google Scholar PubMed
Kanner, S.A., Shuja, Z., Choudhury, P., Jain, A., and Colecraft, H.M. (2020). Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies. Nat. Methods 17: 1245–1253, https://doi.org/10.1038/s41592-020-00992-6.Search in Google Scholar PubMed
Kath, J.E. and Baranczak, A. (2019). Target engagement approaches for pharmacological evaluation in animal models. Chem. Commun. (Cambr) 55: 9241–9250, https://doi.org/10.1039/c9cc02824b.Search in Google Scholar PubMed
Keeley, A., Petri, L., Abranyi-Balogh, P., and Keseru, G.M. (2020). Covalent fragment libraries in drug discovery. Drug Discov. Today 25: 983–996, https://doi.org/10.1016/j.drudis.2020.03.016.Search in Google Scholar PubMed
Kirsch, P., Hartman, A.M., Hirsch, A.K.H., and Empting, M. (2019). Concepts and core principles of fragment-based drug design. Molecules 24: 4309, https://doi.org/10.3390/molecules24234309.Search in Google Scholar PubMed PubMed Central
Komander, D. and Rape, M. (2012). The ubiquitin code. Annu. Rev. Biochem. 81: 203–229, https://doi.org/10.1146/annurev-biochem-060310-170328.Search in Google Scholar PubMed
Kostic, M. and Jones, L.H. (2020). Critical assessment of targeted protein degradation as a research tool and pharmacological modality. Trends Pharmacol. Sci. 41: 305–317, https://doi.org/10.1016/j.tips.2020.02.006.Search in Google Scholar PubMed PubMed Central
Kuljanin, M., Mitchell, D.C., Schweppe, D.K., Gikandi, A.S., Nusinow, D.P., Bulloch, N.J., Vinogradova, E.V., Wilson, D.L., Kool, E.T., Mancias, J.D., et al.. (2021). Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries. Nat. Biotechnol. 39: 630–641, https://doi.org/10.1038/s41587-020-00778-3.Search in Google Scholar PubMed PubMed Central
Labenski, M.T., Bateman, L.A., Voortman, L.T., Giammo, G., Cantin, S., Qiao, L., and Corin, A.F. (2021). SMaSh: a streptavidin mass shift assay for rapidly quantifying target occupancy by irreversible inhibitors. Biochemistry, https://doi.org/10.1021/acs.biochem.1c00422.Search in Google Scholar PubMed
Lai, A.C., Toure, M., Hellerschmied, D., Salami, J., Jaime-Figueroa, S., Ko, E., Hines, J., and Crews, C.M. (2016). Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. 55: 807–810, https://doi.org/10.1002/anie.201507634.Search in Google Scholar PubMed PubMed Central
Lin, S. (2017). Redox-based reagents for chemoselective methionine bioconjugation. Science 355: 597–602, https://doi.org/10.1126/science.aal3316.Search in Google Scholar PubMed PubMed Central
Liu, L., Damerell, D.R., Koukouflis, L., Tong, Y., Marsden, B.D., and Schapira, M. (2019). UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinformatics 35: 2882–2884, https://doi.org/10.1093/bioinformatics/bty1067.Search in Google Scholar PubMed PubMed Central
Liu, Y., Patricelli, M.P., and Cravatt, B.F. (1999). Activity-based protein profiling: the serine hydrolases. Proc. Natl. Acad. Sci. U.S.A. 96: 14694–14699, https://doi.org/10.1073/pnas.96.26.14694.Search in Google Scholar PubMed PubMed Central
Lu, W., Kostic, M., Zhang, T., Che, J., Patricelli, M.P., Jones, L.H., Chouchani, E.T., and Gray, N.S. (2021). Fragment-based covalent ligand discovery. RSC Chem. Biol. 2: 354–367, https://doi.org/10.1039/d0cb00222d.Search in Google Scholar PubMed PubMed Central
Luh, L.M., Scheib, U., Junemann, K., Wortmann, L., Brands, M., and Cromm, P.M. (2020). Prey for the proteasome: targeted protein degradation – a medicinal chemist s perspective. Angew. Chem. Int. Ed. 59: 15448–15466, https://doi.org/10.1002/anie.202004310.Search in Google Scholar PubMed PubMed Central
Luo, M., Spradlin, J.N., Boike, L., Tong, B., Brittain, S.M., McKenna, J.M., Tallarico, J.A., Schirle, M., Maimone, T.J., and Nomura, D.K. (2021). Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem Biol. 28: 559–566, e515, https://doi.org/10.1016/j.chembiol.2021.01.005.Search in Google Scholar PubMed PubMed Central
Main, M.J. and Zhang, A.X. (2020). Advances in cellular target engagement and target deconvolution. SLAS Discov. 25: 115–117, https://doi.org/10.1177/2472555219897269.Search in Google Scholar PubMed
Maurais, A.J. and Weerapana, E. (2019). Reactive-cysteine profiling for drug discovery. Curr. Opin. Chem. Biol. 50: 29–36, https://doi.org/10.1016/j.cbpa.2019.02.010.Search in Google Scholar PubMed PubMed Central
Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., Kaltheuner, I.H., Hahn, E., Seiler, K., Koren, A., et al.. (2020). Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16: 1199–1207, https://doi.org/10.1038/s41589-020-0594-x.Search in Google Scholar PubMed PubMed Central
Metzger, M.B., Hristova, V.A., and Weissman, A.M. (2012). HECT and RING finger families of E3 ubiquitin ligases at a glance. J. Cell Sci. 125: 531–537, https://doi.org/10.1242/jcs.091777.Search in Google Scholar PubMed PubMed Central
Mons, E., Kim, R.Q., van Doodewaerd, B.R., van Veelen, P.A., Mulder, M.P.C., and Ovaa, H. (2021). Exploring the versatility of the covalent thiol-alkyne reaction with substituted propargyl warheads: a deciding role for the cysteine protease. J. Am. Chem. Soc. 143: 6423–6433, https://doi.org/10.1021/jacs.0c10513.Search in Google Scholar PubMed PubMed Central
Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H., and Hakoshima, T. (2018). Structural basis of thalidomide enantiomer binding to cereblon. Sci. Rep. 8: 1294, https://doi.org/10.1038/s41598-018-19202-7.Search in Google Scholar PubMed PubMed Central
Mulder, M.P., Witting, K., Berlin, I., Pruneda, J.N., Wu, K.P., Chang, J.G., Merkx, R., Bialas, J., Groettrup, M., Vertegaal, A.C., et al.. (2016). A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes. Nat. Chem. Biol. 12: 523–530, https://doi.org/10.1038/nchembio.2084.Search in Google Scholar PubMed PubMed Central
Panyain, N., Godinat, A., Lanyon-Hogg, T., Lachiondo-Ortega, S., Will, E.J., Soudy, C., Mondal, M., Mason, K., Elkhalifa, S., Smith, L.M., et al.. (2020). Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with antifibrotic activity. J. Am. Chem. Soc. 142: 12020–12026, https://doi.org/10.1021/jacs.0c04527.Search in Google Scholar PubMed PubMed Central
Pao, K.C., Wood, N.T., Knebel, A., Rafie, K., Stanley, M., Mabbitt, P.D., Sundaramoorthy, R., Hofmann, K., van Aalten, D.M.F., and Virdee, S. (2018). Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556: 381–385, https://doi.org/10.1038/s41586-018-0026-1.Search in Google Scholar PubMed
Petroski, M.D. and Deshaies, R.J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 6: 9–20, https://doi.org/10.1038/nrm1547.Search in Google Scholar PubMed
Pettersson, M. and Crews, C.M. (2019). PROteolysis TArgeting Chimeras (PROTACs) – past, present and future. Drug Discov. Today Technol. 31: 15–27, https://doi.org/10.1016/j.ddtec.2019.01.002.Search in Google Scholar PubMed PubMed Central
Pinch, B.J., Doctor, Z.M., Nabet, B., Browne, C.M., Seo, H.S., Mohardt, M.L., Kozono, S., Lian, X., Manz, T.D., Chun, Y., et al.. (2020). Identification of a potent and selective covalent Pin1 inhibitor. Nat. Chem. Biol. 16: 979–987, https://doi.org/10.1038/s41589-020-0550-9.Search in Google Scholar PubMed PubMed Central
Poole, L.B. (2015). The basics of thiols and cysteines in redox biology and chemistry. Free Radic. Biol. Med. 80: 148–157, https://doi.org/10.1016/j.freeradbiomed.2014.11.013.Search in Google Scholar PubMed PubMed Central
Qi, J., Song, Y., Park, P., Chauhan, D., Wu, L. and Anderson, K. C. (2019). Small molecules for inducing selective protein degradation and uses thereof, International application no. PCT/US2019/019180.Search in Google Scholar
Ray, S. and Murkin, A.S. (2019). New electrophiles and strategies for mechanism-based and targeted covalent inhibitor design. Biochemistry 58: 5234–5244, https://doi.org/10.1021/acs.biochem.9b00293.Search in Google Scholar PubMed
Resnick, E., Bradley, A., Gan, J., Douangamath, A., Krojer, T., Sethi, R., Geurink, P.P., Aimon, A., Amitai, G., Bellini, D., et al.. (2019). Rapid covalent-probe discovery by electrophile-fragment screening. J. Am. Chem. Soc. 141: 8951–8968, https://doi.org/10.1021/jacs.9b02822.Search in Google Scholar PubMed PubMed Central
Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M., and Deshaies, R.J. (2001). Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U.S.A. 98: 8554–8559, https://doi.org/10.1073/pnas.141230798.Search in Google Scholar PubMed PubMed Central
Schauer, N.J., Liu, X., Magin, R.S., Doherty, L.M., Chan, W.C., Ficarro, S.B., Hu, W., Roberts, R.M., Iacob, R.E., Stolte, B., et al.. (2020). Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci. Rep. 10: 5324, https://doi.org/10.1038/s41598-020-62076-x.Search in Google Scholar PubMed PubMed Central
Schneekloth, A.R., Pucheault, M., Tae, H.S., and Crews, C.M. (2008). Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg. Med. Chem. Lett. 18: 5904–5908, https://doi.org/10.1016/j.bmcl.2008.07.114.Search in Google Scholar PubMed PubMed Central
Schrader, E.K., Harstad, K.G., and Matouschek, A. (2009). Targeting proteins for degradation. Nat. Chem. Biol. 5: 815–822, https://doi.org/10.1038/nchembio.250.Search in Google Scholar PubMed PubMed Central
Scott, D.E., Coyne, A.G., Hudson, S.A., and Abell, C. (2012). Fragment-based approaches in drug discovery and chemical biology. Biochemistry 51: 4990–5003, https://doi.org/10.1021/bi3005126.Search in Google Scholar PubMed
Sekine, K., Takubo, K., Kikuchi, R., Nishimoto, M., Kitagawa, M., Abe, F., Nishikawa, K., Tsuruo, T., and Naito, M. (2008). Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J. Biol. Chem. 283: 8961–8968, https://doi.org/10.1074/jbc.m709525200.Search in Google Scholar PubMed
Shraga, A., Resnick, E., Gabizon, R., and London, N. (2021). Covalent fragment screening. In: Ward, R. A. and Grimster, N. P. (Eds.), The design of covalent-based inhibitors, Annual Reports of Medicinal Chemistry, Vol. 56. Academic Press, Cambridge, Massachusetts, pp. 243–265.10.1016/bs.armc.2021.04.001Search in Google Scholar
Singh, J., Petter, R.C., Baillie, T.A., and Whitty, A. (2011). The resurgence of covalent drugs. Nat. Rev. Drug Discov. 10: 307–317, https://doi.org/10.1038/nrd3410.Search in Google Scholar PubMed
Smith, B.E., Wang, S.L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B.D., and Crews, C.M. (2019). Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 10: 131, https://doi.org/10.1038/s41467-018-08027-7.Search in Google Scholar PubMed PubMed Central
Spradlin, J.N., Hu, X., Ward, C.C., Brittain, S.M., Jones, M.D., Ou, L., To, M., Proudfoot, A., Ornelas, E., Woldegiorgis, M., et al.. (2019). Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15: 747–755, https://doi.org/10.1038/s41589-019-0304-8.Search in Google Scholar PubMed PubMed Central
Stefaniak, J., Galan, S.R.G., and Huber, K.V.M. (2021). Assays to characterize the cellular pharmacology of a chemical probe. In: The discovery and utility of chemical probes in target discovery, pp. 247–275.10.1039/9781839160745-00247Search in Google Scholar
Steinebach, C., Ng, Y.L.D., Sosic, I., Lee, C.S., Chen, S., Lindner, S., Vu, L.P., Bricelj, A., Haschemi, R., Monschke, M., et al.. (2020). Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem. Sci. 11: 3474–3486, https://doi.org/10.1039/d0sc00167h.Search in Google Scholar PubMed PubMed Central
Sutanto, F., Konstantinidou, M., and Domling, A. (2020). Covalent inhibitors: a rational approach to drug discovery. RSC Med. Chem. 11: 876–884, https://doi.org/10.1039/d0md00154f.Search in Google Scholar PubMed PubMed Central
Tong, B., Luo, M., Xie, Y., Spradlin, J.N., Tallarico, J.A., McKenna, J.M., Schirle, M., Maimone, T.J., and Nomura, D.K. (2020a). Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci. Rep. 10: 15543, https://doi.org/10.1038/s41598-020-72491-9.Search in Google Scholar PubMed PubMed Central
Tong, B., Spradlin, J.N., Novaes, L.F.T., Zhang, E., Hu, X., Moeller, M., Brittain, S.M., McGregor, L.M., McKenna, J.M., Tallarico, J.A., et al.. (2020b). A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL. ACS Chem. Biol. 15: 1788–1794, https://doi.org/10.1021/acschembio.0c00348.Search in Google Scholar PubMed PubMed Central
Tuley, A. and Fast, W. (2018). The taxonomy of covalent inhibitors. Biochemistry 57: 3326–3337, https://doi.org/10.1021/acs.biochem.8b00315.Search in Google Scholar PubMed PubMed Central
Vinogradova, E.V., Zhang, X., Remillard, D., Lazar, D.C., Suciu, R.M., Wang, Y., Bianco, G., Yamashita, Y., Crowley, V.M., Schafroth, M.A., et al.. (2020). An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 182: 1009–1026, e1029, https://doi.org/10.1016/j.cell.2020.07.001.Search in Google Scholar PubMed PubMed Central
Wang, C., Weerapana, E., Blewett, M.M., and Cravatt, B.F. (2014). A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles. Nat. Methods 11: 79–88, https://doi.org/10.1038/nmeth.2759.Search in Google Scholar PubMed PubMed Central
Ward, C.C., Kleinman, J.I., Brittain, S.M., Lee, P.S., Chung, C.Y.S., Kim, K., Petri, Y., Thomas, J.R., Tallarico, J.A., McKenna, J.M., et al.. (2019). Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. 14: 2430–2440, https://doi.org/10.1021/acschembio.8b01083.Search in Google Scholar PubMed PubMed Central
Ward, J.A., Pinto-Fernandez, A., Cornelissen, L., Bonham, S., Diaz-Saez, L., Riant, O., Huber, K.V.M., Kessler, B.M., Feron, O., and Tate, E.W. (2020). Re-evaluating the mechanism of action of alpha,beta-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein cross-linking with Michael acceptor motif-containing drugs. J. Med. Chem. 63: 3756–3762, https://doi.org/10.1021/acs.jmedchem.0c00144.Search in Google Scholar PubMed PubMed Central
Weerapana, E., Wang, C., Simon, G.M., Richter, F., Khare, S., Dillon, M.B.D., Bachovchin, D.A., Mowen, K., Baker, D., and Cravatt, B.F. (2010). Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468: 790–795, https://doi.org/10.1038/nature09472.Search in Google Scholar PubMed PubMed Central
Wei, J., Meng, F., Park, K.S., Yim, H., Velez, J., Kumar, P., Wang, L., Xie, L., Chen, H., Shen, Y., et al.. (2021). Harnessing the E3 ligase KEAP1 for targeted protein degradation. J. Am. Chem. Soc. 37: 15073–15083, https://doi.org/10.1021/jacs.1c04841.Search in Google Scholar PubMed PubMed Central
Wertz, I.E. and Wang, X. (2019). From discovery to bedside: targeting the ubiquitin system. Cell Chem. Biol. 26: 156–177, https://doi.org/10.1016/j.chembiol.2018.10.022.Search in Google Scholar PubMed
Winter, G.E., Buckley, D.L., Paulk, J., Roberts, J.M., Souza, A., Dhe-Paganon, S., and Bradner, J.E. (2015). Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348: 1376–1381, https://doi.org/10.1126/science.aab1433.Search in Google Scholar PubMed PubMed Central
Wu, H.Q., Baker, D., and Ovaa, H. (2020). Small molecules that target the ubiquitin system. Biochem. Soc. Trans. 48: 479–497, https://doi.org/10.1042/bst20190535.Search in Google Scholar
Zaidman, D., Gehrtz, P., Filep, M., Fearon, D., Gabizon, R., Douangamath, A., Prilusky, J., Duberstein, S., Cohen, G., Owen, C.D., et al.. (2021). An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M(pro) inhibitor. Cell Chem Biol. S2451–9456: 00263–00264, https://doi.org/10.1016/j.chembiol.2021.05.018.Search in Google Scholar PubMed PubMed Central
Zanon, P.R.A., Yu, F., Musacchio, P.Z., Lewald, L., Zollo, M., Krauskopf, K., Mrdović, D., Raunft, P., Maher, T.E., Cigler, M., et al.. (2021). Profiling the proteome-wide selectivity of diverse electrophiles. ChemRXiv.Search in Google Scholar
Zanon, P.R.A., Lewald, L., and Hacker, S.M. (2020). Isotopically labeled desthiobiotin azide (isoDTB) tags enable global profiling of the bacterial cysteinome. Angew. Chem. Int. Ed. 59: 2829–2836, https://doi.org/10.1002/anie.201912075.Search in Google Scholar PubMed PubMed Central
Zengerle, M., Chan, K.H., and Ciulli, A. (2015). Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10: 1770–1777, https://doi.org/10.1021/acschembio.5b00216.Search in Google Scholar PubMed PubMed Central
Zhang, X., Crowley, V.M., Wucherpfennig, T.G., Dix, M.M., and Cravatt, B.F. (2019). Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15: 737–746, https://doi.org/10.1038/s41589-019-0279-5.Search in Google Scholar PubMed PubMed Central
Zhang, X., Luukkonen, L.M., Eissler, C.L., Crowley, V.M., Yamashita, Y., Schafroth, M.A., Kikuchi, S., Weinstein, D.S., Symons, K.T., Nordin, B.E., et al.. (2021). DCAF11 supports targeted protein degradation by electrophilic proteolysis-targeting chimeras. J. Am. Chem. Soc. 143: 5141–5149, https://doi.org/10.1021/jacs.1c00990.Search in Google Scholar PubMed PubMed Central
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