Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening
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Abstract
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.
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A commercial library of 993 acrylamides and chloroacetamides was screened using intact MS to identify ligands of OTUB2 and NUDT7.
“More recently, a commercial library of 993 acrylamides and chloroacetamides was screened using intact MS to identify ligands of the deubiquitinase OTUB2 and the pyrophosphatase NUDT7 (ref.156).”
From Advances in covalent drug discovery (2022) · cites this paper as [156]
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Nonoo, R. H., Armstrong, A., & Mann, D. J. (2012) · ChemMedChem · doi:10.1002/cmdc.201200404 · Cited by 47 · see citing works
Deregulated coenzyme A, loss of metabolic flexibility and diabetes
Jackowski, S., & Leonardi, R. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140156 · Cited by 41 · see citing works
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Self-citationTargeted Covalent Enzyme Inhibitors
Noe, M. C., & Gilbert, A. M. (2012) · Annual reports in medicinal chemistry · doi:10.1016/b978-0-12-396492-2.00027-8 · Cited by 39 · see citing works
Kos, V. N., McLaughlin, R. E., & Gardner, H. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03113-15 · Cited by 39 · see citing works
Applications of Reactive Cysteine Profiling
Backus, K. M. (2018) · Current topics in microbiology and immunology · doi:10.1007/82_2018_120 · Cited by 38 · see citing works
Shumar, S. A., Kerr, E. W., Geldenhuys, W. J., Montgomery, G. E., Fagone, P., Thirawatananond, P., Saavedra, H. G., Gabelli, S. B., & Leonardi, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001358 · Cited by 37 · see citing works
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Probing structural adaptivity at PPI interfaces with small molecules
Wilson, C. G. M., & Arkin, M. R. (2012) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2012.10.009 · Cited by 22 · see citing works
USP8: a novel therapeutic target for Cushing’s disease
Jian, F., Cao, Y., Bian, L., & Sun, Q. (2015) · Endocrine · doi:10.1007/s12020-015-0682-y · Cited by 14 · see citing works
Grossman, I., Ilani, T., Fleishman, S. J., & Fass, D. (2016) · Protein Engineering Design and Selection · doi:10.1093/protein/gzv067 · Cited by 14 · see citing works
Chemical proteomics and its application to drug discovery.
Jeffery, D. A., & Bogyo, M. S. (2004) · PubMed · Cited by 7 · see citing works
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Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T. J., Lukacik, P., Owen, C. D., Resnick, E., Strain-Damerell, C. M., Aimon, A., Ábrányi‐Balogh, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18709-w · Cited by 541 · see citing works
Self-citationAdvances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Henley, M. J., & Koehler, A. N. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00199-0 · Cited by 409 · see citing works
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones
Ishida, T., & Ciulli, A. (2020) · SLAS DISCOVERY · doi:10.1177/2472555220965528 · Cited by 395 · see citing works
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) · Nature Biotechnology · doi:10.1038/s41587-020-00778-3 · Cited by 305 · see citing works
Chemistries of bifunctional PROTAC degraders
Cao, C., He, M., Wang, L., He, Y., & Rao, Y. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00220e · Cited by 313 · see citing works
Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update
Hillebrand, L., Liang, X. J., Serafim, R. A. M., & Gehringer, M. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01825 · Cited by 212 · see citing works
PROTACs to address the challenges facing small molecule inhibitors
Martín-Acosta, P., & Xiao, X. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112993 · Cited by 186 · see citing works
Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation
Zhang, T., Hatcher, J. M., Teng, M., Gray, N. S., & Kostic, M. (2019) · Cell Chemical Biology · doi:10.1016/j.chembiol.2019.09.012 · Cited by 178 · see citing works
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Boby, M. L., Fearon, D., Ferla, M., Filep, M., Koekemoer, L., Robinson, M. C., Chodera, J. D., Lee, A. A., London, N., von Delft, A., et al. (2023) · Science · doi:10.1126/science.abo7201 · Cited by 231 · see citing works
Self-citationReimagining Druggability Using Chemoproteomic Platforms
Spradlin, J. N., Zhang, E., & Nomura, D. K. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00065 · Cited by 176 · see citing works
Bzówka, M., Mitusińska, K., Raczyńska, A., Samol, A., Tuszyński, J. A., & Góra, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093099 · Cited by 172 · see citing works
Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo
Dubiella, C., Pinch, B. J., Koikawa, K., Zaidman, D., Poon, E., Manz, T. D., Nabet, B., He, S., Resnick, E., Rogel, A., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00786-7 · Cited by 161 · see citing works
Self-citationDiscovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC
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. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.09.001 · Cited by 154 · see citing works
The role of reversible and irreversible covalent chemistry in targeted protein degradation
Kiely‐Collins, H., Winter, G. E., & Bernardes, G. J. L. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.005 · Cited by 156 · see citing works
Fragment‐based drug discovery—the importance of high‐quality molecule libraries
Bon, M., Bilsland, A. E., Bower, J. F., & McAulay, K. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13277 · Cited by 153 · see citing works
Tokunaga, K., Sato, M., Kuwata, K., Miura, C., Fuchida, H., Matsunaga, N., Koyanagi, S., Ohdo, S., Shindo, N., & Ojida, A. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c07490 · Cited by 145 · see citing works
Fragment-based covalent ligand discovery
Lu, W., Kostic, M., Zhang, T., Che, J., Patricelli, M. P., Jones, L. H., Chouchani, E. T., & Gray, N. S. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00222d · Cited by 136 · see citing works
10 Years Into the Resurgence of Covalent Drugs
Vita, E. D. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0236 · Cited by 125 · see citing works
Advances in high‐throughput mass spectrometry in drug discovery
Dueñas, M. E., Heap, R. E., Leveridge, M. V., Annan, R. S., Büttner, F. H., & Trost, M. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202114850 · Cited by 124 · see citing works
Tunable Heteroaromatic Sulfones Enhance in-Cell Cysteine Profiling
Motiwala, H. F., Kuo, Y.-H., Stinger, B. L., Palfey, B. A., & Martin, B. R. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b08831 · Cited by 125 · see citing works
Mons, E., Roet, S., Kim, R. Q., & Mulder, M. P. C. (2022) · Current Protocols · doi:10.1002/cpz1.419 · Cited by 123 · see citing works
Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development
Huang, F., Han, X., Xiao, X., & Zhou, J. (2022) · Molecules · doi:10.3390/molecules27227728 · Cited by 123 · see citing works
Regulation of coenzyme A levels by degradation: the ‘Ins and Outs’
Naquet, P., Kerr, E. W., Vickers, S. D., & Leonardi, R. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101028 · Cited by 115 · see citing works
2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles
Zambaldo, C., Vinogradova, E. V., Qi, X., Iaconelli, J., Suciu, R. M., Koh, M., Senkane, K., Chadwick, S. R., Sanchez, B. B., Chen, J. S., et al. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c02721 · Cited by 114 · see citing works
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2
Sanders, B., Pokhrel, S., Labbe, A. D., Mathews, I. I., Cooper, C. J., Davidson, R. B., Phillips, G., Weiss, K. L., Zhang, Q., O’Neill, H., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37254-w · Cited by 114 · see citing works
Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes
Hartung, I. V., Rudolph, J., Mader, M. M., Mulder, M. P. C., & Workman, P. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00550 · Cited by 109 · see citing works
Gilbert, K. E., Vuorinen, A., Aatkar, A., Pogány, P., Pettinger, J., Grant, E. K., Kirkpatrick, J. M., Rittinger, K., House, D., Burley, G. A., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.2c00633 · Cited by 100 · see citing works
Covalent fragment libraries in drug discovery
Keeley, A. B., Petri, L., Ábrányi‐Balogh, P., & Keserű, G. M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.03.016 · Cited by 104 · see citing works
Liganding Functional Tyrosine Sites on Proteins Using Sulfur–Triazole Exchange Chemistry
Brulet, J. W., Borne, A. L., Yuan, K., Libby, A. H., & Hsu, K. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c00648 · Cited by 105 · see citing works
Strategies for targeting undruggable targets
Zhang, G., Zhang, J., Gao, Y., Li, Y., & Li, Y. (2021) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2021.1969359 · Cited by 102 · see citing works
Covalent Small Molecules as Enabling Platforms for Drug Discovery
Dalton, S. E., & Campos, S. (2019) · ChemBioChem · doi:10.1002/cbic.201900674 · Cited by 98 · see citing works
Keeley, A. B., Ábrányi-Balogh, P., & Keserű, G. M. (2018) · MedChemComm · doi:10.1039/c8md00327k · Cited by 95 · see citing works
A direct-to-biology high-throughput chemistry approach to reactive fragment screening
Thomas, R. P., Heap, R. E., Zappacosta, F., Grant, E. K., Pogány, P., Besley, S., Fallon, D. J., Hann, M. M., House, D., Tomkinson, N. C. O., et al. (2021) · Chemical Science · doi:10.1039/d1sc03551g · Cited by 92 · see citing works
Zaidman, D., Gehrtz, P., Filep, M., Fearon, D., Gabizon, R., Douangamath, A., Prilusky, J., Duberstein, S., Cohen, G., Owen, C. D., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.05.018 · Cited by 85 · see citing works
Self-citationKooij, R., Liu, S., Sapmaz, A., Xin, B.-T., Janssen, G. M. C., van Veelen, P. A., Ovaa, H., Dijke, P. T., & Geurink, P. P. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c07726 · Cited by 82 · see citing works
Self-citationTargeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B
Skaist Mehlman, T., Biel, J. T., Azeem, S. M., Nelson, E. R., Hossain, S., Dunnett, L., Paterson, N. G., Douangamath, A., Talon, R., Axford, D., et al. (2023) · eLife · doi:10.7554/elife.84632 · Cited by 84 · see citing works
Self-citationChemoproteomic methods for covalent drug discovery
Chan, W. C., Sharifzadeh, S., Buhrlage, S. J., & Marto, J. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00231g · Cited by 78 · see citing works
Fragment-to-Lead Medicinal Chemistry Publications in 2019
Jahnke, W., Erlanson, D. A., de Esch, I. J. P., Johnson, C. N., Mortenson, P. N., Ochi, Y., & Urushima, T. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01608 · Cited by 73 · see citing works
Mons, E., Kim, R. Q., van Doodewaerd, B. R., van Veelen, P. A., Mulder, M. P. C., & Ovaa, H. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.0c10513 · Cited by 72 · see citing works
Self-citationNicotinamide N-methyl transferase (NNMT): An emerging therapeutic target
Gao, Y., Martin, N. I., & van Haren, M. J. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.05.011 · Cited by 72 · see citing works
Development of covalent inhibitors: Principle, design, and application in cancer
Zheng, L., Li, Y., Wu, D., Xiao, H., Zheng, S., Wang, G., & Sun, Q. (2023) · MedComm – Oncology · doi:10.1002/mog2.56 · Cited by 71 · see citing works
The rise of covalent proteolysis targeting chimeras
Gabizon, R., & London, N. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.12.003 · Cited by 70 · see citing works
Self-citationCovalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
Fan, M., Lu, W., Che, J., Kwiatkowski, N. P., Gao, Y., Seo, H.-S., Ficarro, S. B., Gokhale, P. C., Liu, Y., Geffken, E. A., et al. (2022) · eLife · doi:10.7554/elife.78810 · Cited by 68 · see citing works
Recent progress in covalent warheads for in vivo targeting of endogenous proteins
Shindo, N., & Ojida, A. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116386 · Cited by 66 · see citing works
Applications of covalent chemistry in targeted protein degradation
Lu, D., Yu, X., Lin, H., Cheng, R., Monroy, E. Y., Qi, X., Wang, M. C., & Wang, J. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00362g · Cited by 66 · see citing works
High-Throughput Cellular Thermal Shift Assays in Research and Drug Discovery
Henderson, M. J., Holbert, M. A., Simeonov, A. M., & Kallal, L. A. (2019) · SLAS DISCOVERY · doi:10.1177/2472555219877183 · Cited by 67 · see citing works
Fragment-based drug discovery supports drugging ‘undruggable’ protein–protein interactions
Wang, Z.-Z., Shi, X.-X., Huang, G.-Y., Hao, G., & Yang, G. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.01.008 · Cited by 64 · see citing works
A Photoaffinity‐Based Fragment‐Screening Platform for Efficient Identification of Protein Ligands
Grant, E. K., Fallon, D. J., Hann, M. M., Fantom, K. G. M., Quinn, C. J., Zappacosta, F., Annan, R. S., Chung, C., Bamborough, P., Dixon, D. P., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202008361 · Cited by 59 · see citing works
Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease InhibitorsPreprint
Boby, M. L., Fearon, D., Ferla, M. P., Filep, M., Koekemoer, L., Robinson, M. C., Chodera, J. D., Lee, A. A., London, N., von Delft, A., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.29.339317 · Cited by 59 · see citing works
Self-citationKawano, M., Murakawa, S., Higashiguchi, K., Matsuda, K., Tamura, T., & Hamachi, I. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c08740 · Cited by 58 · see citing works
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions
Cossar, P. J., Wolter, M., Dijck, L. V., Valenti, D., Levy, L. M., Ottmann, C., & Brunsveld, L. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03035 · Cited by 56 · see citing works
Osborne, J., Panova, S., Rapti, M., Urushima, T., & Jhoti, H. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190694 · Cited by 59 · see citing works
Functionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization
Crowley, V. M., Thielert, M., & Cravatt, B. F. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01336 · Cited by 53 · see citing works
CovPDB: a high-resolution coverage of the covalent protein–ligand interactome
Gao, M., Moumbock, A. F. A., Qaseem, A., Xu, Q., & Günther, S. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab868 · Cited by 51 · see citing works
Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments
Aatkar, A., Vuorinen, A., Longfield, O., Gilbert, K. E., Heap, R. E., Wagner, C. D., Zappacosta, F., Rittinger, K., Chung, C., House, D., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00034 · Cited by 51 · see citing works
Dai, L., Li, Z., Chen, D., Jia, L., Guo, J., Zhao, T., & Nordlund, P. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107690 · Cited by 52 · see citing works
Self-citationA guide to enzyme kinetics in early drug discovery
Srinivasan, B. (2022) · FEBS Journal · doi:10.1111/febs.16404 · Cited by 51 · see citing works
Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery
McAulay, K., Bilsland, A. E., & Bon, M. (2022) · Pharmaceuticals · doi:10.3390/ph15111366 · Cited by 50 · see citing works
Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry
Reddi, R. N., Rogel, A., Gabizon, R., Rawale, D. G., Harish, B., Marom, S., Tivon, B., Arbel, Y. S., Gurwicz, N., Oren, R., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08853 · Cited by 49 · see citing works
Self-citationBzówka, M., Mitusińska, K., Raczyńska, A., Samol, A., Tuszyński, J. A., & Góra, A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.27.968008 · Cited by 49 · see citing works
Multicomponent reaction–derived covalent inhibitor space
Sutanto, F., Shaabani, S., Neochoritis, C. G., Zarganes‐Tzitzikas, T., Patil, P., Ghonchepour, E., & Dömling, A. S. S. (2021) · Science Advances · doi:10.1126/sciadv.abd9307 · Cited by 48 · see citing works
Gonzalez-Valero, A., Reeves, A. G., Page, A. C. S., Moon, P. J., Miller, E., Coulonval, K., Crossley, S. W. M., Xie, X., He, D., Musacchio, P. Z., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c04039 · Cited by 47 · see citing works
Olp, M. D., Sprague, D. J., Goetz, C. J., Kathman, S. G., Wynia‐Smith, S. L., Shishodia, S., Summers, S. B., Xu, Z., Statsyuk, A. V., & Smith, B. C. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00058 · Cited by 47 · see citing works
Identification of Covalent Cyclic Peptide Inhibitors in mRNA Display
Iskandar, S. E., Chiou, L. F., Leisner, T. M., Shell, D. J., Norris-Drouin, J. L., Vaziri, C., Pearce, K. H., & Bowers, A. A. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c04833 · Cited by 43 · see citing works
Carbery, A., Skyner, R., von Delft, F., & Deane, C. M. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01004 · Cited by 41 · see citing works
Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
Ge, R., Shen, Z., Yin, J., Chen, W., Zhang, Q., An, Y., Tang, D., Satz, A. L., Su, W., & Kuai, L. (2022) · SLAS DISCOVERY · doi:10.1016/j.slasd.2022.01.001 · Cited by 43 · see citing works
Tallon, A. M., Xu, Y., West, G. M., am Ende, C. W., & Fox, J. M. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c04444 · Cited by 43 · see citing works
Development and biological applications of sulfur–triazole exchange (SuTEx) chemistry
Borne, A. L., Brulet, J. W., Yuan, K., & Hsu, K. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00180e · Cited by 42 · see citing works
Abegg, D., Tomanik, M., Qiu, N., Pechalrieu, D., Shuster, A., Commare, B., Togni, A., Herzon, S. B., & Adibekian, A. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c09724 · Cited by 40 · see citing works
Advanced approaches of developing targeted covalent drugs
Gai, C., Harnor, S. J., Zhang, S., Cano, C., Zhuang, C., & Zhao, Q. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00216g · Cited by 42 · see citing works
Somsen, B. A., Schellekens, R. J. C., Verhoef, C. J. A., Arkin, M. R., Ottmann, C., Cossar, P. J., & Brunsveld, L. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c12781 · Cited by 41 · see citing works
Small molecules that target the ubiquitin system
Wu, H. Q., Baker, D. A., & Ovaa, H. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190535 · Cited by 41 · see citing works
Self-citationBianco, G., Goodsell, D. S., & Forli, S. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.10.005 · Cited by 39 · see citing works
Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes
Huang, T., Hosseinibarkooie, S., Borne, A. L., Granade, M. E., Brulet, J. W., Harris, T. E., Ferris, H. A., & Hsu, K. (2021) · Chemical Science · doi:10.1039/d0sc06623k · Cited by 41 · see citing works
Open science approaches to COVID-19
Tse, E. G., Klug, D. M., & Todd, M. H. (2020) · F1000Research · doi:10.12688/f1000research.26084.1 · Cited by 39 · see citing works
Discovery of allosteric binding sites by crystallographic fragment screening
Krojer, T. J., Fraser, J. S., & von Delft, F. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.08.004 · Cited by 39 · see citing works
Self-citationLondon, N. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00570 · Cited by 36 · see citing works
Self-citationShumar, S. A., Kerr, E. W., Geldenhuys, W. J., Montgomery, G. E., Fagone, P., Thirawatananond, P., Saavedra, H. G., Gabelli, S. B., & Leonardi, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001358 · Cited by 37 · see citing works
Library Design Strategies To Accelerate Fragment‐Based Drug Discovery
Troelsen, N. S., & Clausen, M. H. (2020) · Chemistry - A European Journal · doi:10.1002/chem.202000584 · Cited by 37 · see citing works
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Molecular glue degraders: exciting opportunities for novel drug discovery
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- Authors
- Resnick, E., Bradley, A., Gan, J., Douangamath, A., Krojer, T., Sethi, R., Geurink, P. P., Aimon, A., Amitai, G., Bellini, D., Bennett, J., Fairhead, M., Fedorov, O., Gabizon, R., Gan, J., Guo, J., Plotnikov, A., Reznik, N., Ruda, G. F., Díaz-Sáez, L., Straub, V. M., Szommer, T., Velupillai, S., Zaidman, D., Zhang, Y., Coker, A. R., Dowson, C. G., Barr, H. M., Wang, C., Huber, K. V. M., Brennan, P. E., Ovaa, H., von Delft, F., & London, N.
- Affiliations
- Weizmann Institute of Science (IL)
- Diamond Light Source (GB)
- Leiden University Medical Center (NL)
- University of Oxford (GB)
- Vrije Universiteit Brussel (BE)
- University of Warwick (GB)
- University College London (GB)
- University of Oxford , , , ,
- Peking University (CN)
- Corresponding author
- London, Nir
- ORCID
- Resnick, Efrat
- Bradley, Anthony
- Douangamath, Alice
- Krojer, Tobias
- Sethi, Ritika
- Geurink, Paul P.
- Aimon, Anthony
- Bellini, Dom
- Bennett, James
- Fairhead, Michael
- Fedorov, Oleg
- Gabizon, Ronen
- Guo, Jingxu
- Plotnikov, Alexander
- Reznik, Nava
- Ruda, Gian Filippo
- Straub, Verena M.
- Velupillai, Srikannathasan
- Zaidman, Daniel
- Zhang, Yanling
- Coker, Alun R.
- Dowson, Christopher G.
- Barr, Haim M.
- Wang, Chu
- Huber, Kilian V.M.
- Brennan, Paul E.
- Ovaa, Huib
- London, Nir
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-07
- Volume
- 141
- Issue
- 22
- Pages
- 8951-8968
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC6556873
- OpenAlex
- W2949252818
- Cited by
- 335
- References
- 100
- Citations by year
- 2026: 40 · 2025: 39 · 2024: 51 · 2023: 58 · 2022: 45 · 2021: 50 · 2020: 42 · 2019: 8 · 2018: 2
- FWCI
- 14.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Israel Cancer Research Fund (NA)
- Wellcome Trust (106169/Z/14/Z)
- Ontario Genomics Institute (OGI-055)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (724.013.002)
- Israel Science Foundation (1097/16)
- Ministry of Science and Technology, Israel (3-14763)
- Innovative Medicines Initiative (115766, NA)
- Rising Tide Foundation (NA)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- covalent probes, fragment-based drug discovery, cysteine-containing proteins, OTUB2, NUDT7, deubiquitinase inhibitors, high-throughput crystallography
- MeSH terms
- Drug Evaluation, Preclinical, Electrons, Humans, Ligands, Models, Molecular, Molecular Weight, Protein Conformation, Time Factors, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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