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Proteome-wide covalent ligand discovery in native biological systems
Open accessAbstract
Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered 'undruggable'. Fragment-based ligand discovery can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes, including those that can access regions of proteins that are difficult to target through binding affinity alone. Here we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins in human proteomes and cells. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and -10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems.
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“Although human CASP10 shares some degree of substrate specificity with CASP8 [317] and possibly contributes to extrinsic apoptosis in primary T cells [318]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [318]
In the citing paper
“Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [53]
In the citing paper
“Reactive cysteine residues on proteins have high nucleophilicity, which enables covalent binding with electrophilic small molecules [53, 54].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [53]
In the citing paper
“In this study, more than 700 ligandable cysteines were identified, and information was provided about the proteome-wide selectivity of each covalent fragment in the library.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“The use of competitive isoTOP-ABPP was expanded to identify proteome-wide targets of a small covalent fragment library by competing individual acrylamide and chloroacetamide fragments against an iodoacetamide–alkyne probe180.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“showing that this approach can rapidly identify compounds that target proteins of biological interest.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“The covalent ligands discovered with this approach and their corresponding ligandable sites were used to help elucidate the role of caspase 8 and caspase 10 in extrinsic apoptosis in T cells”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“We finally observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine-26,27 or lysine-reactive28 electrophilic fragments (Fig. 3b)”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [26]
In the citing paper
“prior to further processing using a well-validated method for covalent ligand target identification—isotopic tandem orthogonal proteolysis ABPP (isoTOP-ABPP) 2,17,26.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [2]
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Citations
Cites
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21256 · Cited by 26,294
Self-citationBLAST+: architecture and applications
Camacho, C., Coulouris, G., Avagyan, V., Ma, N., Papadopoulos, J., Bealer, K., & Madden, T. L. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-421 · Cited by 22,074
Open Babel: An open chemical toolbox
O'Boyle, N. M., Banck, M. S., James, C. A. J., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011) · Journal of Cheminformatics · doi:10.1186/1758-2946-3-33 · Cited by 10,745
The I-TASSER Suite: protein structure and function prediction
Yang, J., Yan, R., Roy, A., Xu, D., Poisson, J., & Zhang, Y. (2015) · Nature Methods · doi:10.1038/nmeth.3213 · Cited by 5,596
UniProt: a hub for protein information
The UniProt Consortium (2015) · Nucleic Acids Research · doi:10.1093/nar/gku989 · Cited by 5,106
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
DrugBank 4.0: shedding new light on drug metabolism
Law, V., Knox, C., Djoumbou-Feunang, Y., Jewison, T., Guo, A. C., Liu, Y., Maciejewski, A., Arndt, D., Wilson, M., Neveu, V., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1068 · Cited by 1,995
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Activity-based protein profiling: Recent advances in medicinal chemistry
Deng, H., Lei, Q., Wu, Y., He, Y., & Li, W. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112151 · Cited by 125
Targeted protein acetylation in cells using heterobifunctional molecules
Wang, W. W., Chen, L.-Y., Wozniak, J. M., Jadhav, A. M., Anderson, H., Malone, T. E., & Parker, C. G. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c07850 · Cited by 114
Chemoproteomic Screening of Covalent Ligands Reveals UBA5 As a Novel Pancreatic Cancer Target
Roberts, A. M., Miyamoto, D. K., Huffman, T. R., Bateman, L. A., Ives, A. N., Akopian, D., Heslin, M. J., Contreras, C. M., Rapé, M., Skibola, C. F., et al. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00020 · Cited by 113
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 121
“We next evaluated a core subset of these analogs (1, 5, 7-10) for in vitro reactivity with reduced glutathione (GSH) and for ARE-LUC inducing activity in reporter assays.”
MethodSelf-citationBenns, H. J., Wincott, C. J., Tate, E. W., & Child, M. A. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.06.011 · Cited by 112
Roberts, A. M., Ward, C. C., & Nomura, D. K. (2017) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2016.08.003 · Cited by 108
“Furthermore, while covalent inhibitors have been historically frowned upon due to their potential non-selective reactivity, coupling the development of inhibitors with chemoproteomic platforms such as ABPP enables the synthesis of potent and selective covalent inhibitors against protein targets through ABPP driving th…”
Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors
Dahlin, J. L., Nelson, K. M., Strasser, J. M., Baršytė-Lovejoy, D., Szewczyk, M. M., Organ, S. L., Cuellar, M. E., Singh, G., Shrimp, J. H., Nguyen, N. H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01657-3 · Cited by 109
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 105
Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
Mateus, A., Gordon, L. J., Wayne, G. J., Almqvist, H., Axelsson, H., Seashore-Ludlow, B. A., Treyer, A., Matsson, P., Lundbäck, T., West, A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701848114 · Cited by 106
Paxman, R. J., Plate, L., Blackwood, E. A., Glembotski, C. C., Powers, E. T., Wiseman, R. L., & Kelly, J. W. (2018) · eLife · doi:10.7554/elife.37168 · Cited by 107
A high throughput screen for next-generation leads targeting malaria parasite transmission
Delves, M. J., Miguel-Blanco, C., Matthews, H., Molina, I., Ruecker, A., Yahiya, S., Straschil, U., Abraham, M., León, M. L., Fischer, O. J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05777-2 · Cited by 106
Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19
Steuten, K., Kim, H., Widen, J. C., Babin, B. M., Onguka, O., Lovell, S., Bolgi, O., Cerikan, B., Neufeldt, C. J., Cortese, M., et al. (2021) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.0c00815 · Cited by 103
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Takahashi, M., Chong, H. B., Zhang, S., Yang, T.-Y., Lazarov, M. J., Harry, S. A., Maynard, M., Hilbert, B. J., White, R. D., Murrey, H. E., et al. (2024) · Cell · doi:10.1016/j.cell.2024.03.027 · Cited by 110
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
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 110
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 107
Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB
King, E. A., Cho, Y. J., Hsu, N. T., Dovala, D., McKenna, J. M., Tallarico, J. A., Schirle, M., & Nomura, D. K. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.02.008 · Cited by 107
Emerging targetome and signalome landscape of gut microbial metabolites
Zheng, X., Cai, X., & Hao, H. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.12.011 · Cited by 100
Isotopically-Labeled Iodoacetamide-Alkyne Probes for Quantitative Cysteine-Reactivity Profiling
Abo, M., Li, C., & Weerapana, E. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b00832 · Cited by 104
Advanced Activity-Based Protein Profiling Application Strategies for Drug Development
Wang, S., Tian, Y., Wang, M., Wang, M., Sun, G., & Sun, X. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00353 · Cited by 108
“Iodoacetamide is a reagent classically used to react with cysteine and is often seen in proteomics; so, the Cravatt group used iodoacetamide to design a probe (Backus et al., 2016).”
MethodPhotoaffinity labelling strategies for mapping the small molecule–protein interactome
Burton, N. R., Kim, P., & Backus, K. M. (2021) · Organic & Biomolecular Chemistry · doi:10.1039/d1ob01353j · Cited by 106
Self-citationDCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders
Lim, M., Cong, T. D., Orr, L. M., Toriki, E. S., Kile, A. C., Papatzimas, J. W., Lee, E., Lin, Y., & Nomura, D. K. (2024) · ACS Central Science · doi:10.1021/acscentsci.4c00286 · Cited by 106
“E3 ligases have been shown to be ligandable with covalent small-molecules and chemoproteomic approaches 10– 16 .”
BackgroundCovalent Protein Labeling at Glutamic Acids
Martín‐Gago, P., Fansa, E. K., Winzker, M., Murarka, S., Janning, P., Schultz‐Fademrecht, C., Baumann, M., Wittinghofer, A., & Waldmann, H. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.03.015 · Cited by 99
Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors
Niessen, S., Dix, M. M., Barbas, S., Potter, Z. E., Lu, S., Brodsky, O., Planken, S., Behenna, D. C., Almaden, C., Gajiwala, K. S., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.017 · Cited by 99
“The isoTOP sample prep was carried out as previously described (Backus et al., 2016, Weerapana et al., 2010).”
BackgroundMethodInfluentialSelf-citationCovalent Small Molecules as Enabling Platforms for Drug Discovery
Dalton, S. E., & Campos, S. (2019) · ChemBioChem · doi:10.1002/cbic.201900674 · Cited by 101
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Reddi, R. N., Resnick, E., Rogel, A., Rao, B. V., Gabizon, R., Goldenberg, K., Gurwicz, N., Zaidman, D., Plotnikov, A. N., Barr, H. M., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.0c10644 · Cited by 99
CysDB: a human cysteine database based on experimental quantitative chemoproteomics
Boatner, L. M., Palafox, M. F., Schweppe, D. K., & Backus, K. M. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.04.004 · Cited by 99
Self-citationExpanding the scope of electrophiles capable of targeting K-Ras oncogenes
McGregor, L. M., Jenkins, M. L., Kerwin, C., Burke, J. E., & Shokat, K. M. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00271 · Cited by 97
Chemical Proteomic Profiling of Human Methyltransferases
Horning, B. D., Suciu, R. M., Ghadiri, D. A., Ulanovskaya, O. A., Matthews, M. L., Lum, K. M., Backus, K. M., Brown, S. J., Rosen, H., & Cravatt, B. F. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b07830 · Cited by 97
Self-citationKeeley, A. B., Ábrányi-Balogh, P., & Keserű, G. M. (2018) · MedChemComm · doi:10.1039/c8md00327k · Cited by 95
The design and development of covalent protein-protein interaction inhibitors for cancer treatment
Cheng, S.-S., Yang, G.-J., Wang, W., Leung, C.-H., & Ma, D.-L. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00850-0 · Cited by 98
Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells
Offensperger, F., Tin, G., Duran‐Frigola, M., Hahn, E., Dobner, S., Ende, C. W. A., Strohbach, J. W., Rukavina, A., Brennsteiner, V., Ogilvie, K., et al. (2024) · Science · doi:10.1126/science.adk5864 · Cited by 102
“Initial efforts predominantly focused on electrophilic fragments ( 11 – 15 ).”
BackgroundParthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells
Berdan, C. A., Ho, R. Y., Lehtola, H. S., To, M., Hu, X., Huffman, T. R., Petri, Y. D., Altobelli, C. R., Demeulenaere, S. K., Olzmann, J. A., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.03.016 · Cited by 94
Redox regulation of macrophages
Tran, N., & Mills, E. L. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103123 · Cited by 101
“In particular, this method has been applied to identify cysteine targets of small-molecule covalent drugs [298 – 300] or to discover targetable cysteine sites in “ undruggable ” proteins [301].”
MethodCaspase-8 in inflammatory diseases: a potential therapeutic target
Zhang, W., Zhu, C., Liao, Y., Zhou, M., Xu, W., & Zou, Z. (2024) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00646-x · Cited by 108
“For example, caspase-10 plays a critical role in mediating various cell death pathways, including apoptosis, pyroptosis, and necroptosis [315, 316].”
BackgroundChan, A. I., McGregor, L. M., Jain, T., & Liu, D. R. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b04880 · Cited by 92
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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 93
A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification
Browne, C. M., Jiang, B., Ficarro, S. B., Doctor, Z. M., Johnson, J. L., Card, J. D., Sivakumaren, S. C., Alexander, W. M., Yaron, T. M., Murphy, C. J., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b07911 · Cited by 94
Identification of a potent and selective covalent Pin1 inhibitor
Pinch, B. J., Doctor, Z. M., Nabet, B., Browne, C. M., Seo, H., Mohardt, M. L., Kozono, S., Lian, X., Manz, T. D., Chun, Y., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0550-9 · Cited by 90
SP3‐FAIMS Chemoproteomics for High‐Coverage Profiling of the Human Cysteinome**
Yan, T., Desai, H. S., Boatner, L. M., Yen, S. L., Cao, J. X., Palafox, M. F., Jami‐Alahmadi, Y., & Backus, K. M. (2021) · ChemBioChem · doi:10.1002/cbic.202000870 · Cited by 90
Self-citationElectrophilic warheads in covalent drug discovery: an overview
Péczka, N., Orgován, Z., Ábrányi‐Balogh, P., & Keserű, G. M. (2022) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2022.2034783 · Cited by 92
Privileged Electrophile Sensors: A Resource for Covalent Drug Development
Long, M. J. C., & Aye, Y. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.05.023 · Cited by 81
Modeling covalent-modifier drugs.
Awoonor-Williams, E., Walsh, A. G., & Rowley, C. N. (2017) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2017.05.009 · Cited by 90
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
Single-site glycine-specific labeling of proteins
Purushottam, L., Adusumalli, S. R., Singh, U., Unnikrishnan, V. B., Rawale, D. G., Gujrati, M., Mishra, R. K., & Rai, V. (2019) · Nature Communications · doi:10.1038/s41467-019-10503-7 · Cited by 87
Accelerating inhibitor discovery for deubiquitinating enzymes
Chan, W. C., Liu, X., Magin, R. S., Girardi, N. M., Ficarro, S. B., Hu, W., Guzman, M. I. T., Starnbach, C. A., Felix, A., Adelmant, G., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36246-0 · Cited by 85
Proteomic discovery of chemical probes that perturb protein complexes in human cells
Lazear, M. R., Remsberg, J. R., Jaeger, M. G., Rothamel, K. L., Her, H.-L., DeMeester, K. E., Njomen, E., Hogg, S. J., Rahman, J. A., Whitby, L. R., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.03.026 · Cited by 85
Self-citationQuantitative Chemoproteomic Profiling with Data-Independent Acquisition-Based Mass Spectrometry
Yang, F., Jia, G., Guo, J., Liu, Y., & Wang, C. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c11053 · Cited by 84
Ligand discovery by activity-based protein profiling
Niphakis, M. J., & Cravatt, B. F. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.08.006 · Cited by 93
Self-citationFu, L., Li, Z., Liu, K., Tian, C., He, J.-X., He, J., He, F., Xu, P., & Yang, J. H. (2020) · Nature Protocols · doi:10.1038/s41596-020-0352-2 · Cited by 88
Instrumentation at the Leading Edge of Proteomics
Peters-Clarke, T. M., Coon, J. J., & Riley, N. M. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c04497 · Cited by 89
Strategic Design of Catalytic Lysine‐Targeting Reversible Covalent BCR‐ABL Inhibitors**
Quach, D., Tang, G., Anantharajan, J., Baburajendran, N., Poulsen, A., Wee, J. L. K., Retna, P., Li, R., Liu, B., Tee, D. H. Y., et al. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202105383 · Cited by 84
Remodeling oncogenic transcriptomes by small molecules targeting NONO
Kathman, S. G., Koo, S. J., Lindsey, G. L., Her, H.-L., Blue, S. M., Li, H., Jaensch, S., Remsberg, J. R., Ahn, K., Yeo, G. W.-M., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01270-0 · Cited by 84
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Kavanagh, M. E., Horning, B. D., Khattri, R., Roy, N., Lu, J. P., Whitby, L. R., Ye, E., Brannon, J. C., Parker, A., Chick, J. M., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01098-0 · Cited by 85
“Finally, we believe that our findings provide another compelling example of the utility of chemical proteomics for discovering small molecules that act by unconventional mechanisms 20,48–50 .”
Self-citationSelective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain
Feldman, H. C., Merlini, E., Guijas, C., DeMeester, K. E., Njomen, E., Kozina, E. M., Yokoyama, M., Vinogradova, E. V., Reardon, H. T., Melillo, B. N., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208457119 · Cited by 79
Self-citationHigh‐Throughput Kinetic Analysis for Target‐Directed Covalent Ligand Discovery
Craven, G. B., Affron, D. P., Allen, C. E., Matthies, S., Greener, J. G., Morgan, R. M. L., Tate, E. W., Armstrong, A., & Mann, D. J. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201711825 · Cited by 73
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Du, H., Gao, J., Weng, G., Ding, J., Chai, X., Pang, J., Kang, Y., Li, D., Cao, D., & Hou, T. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa876 · Cited by 74
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Gao, D., Vinogradova, E. V., Nimmagadda, S. K., Medina, J. M., Xiao, Y., Suciu, R. M., Cravatt, B. F., & Engle, K. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b03704 · Cited by 76
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 80
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“, thioredoxin reductase) to afford irreversible inhibition, leading to potential non-targeting effects and clinical safety issues [47].”
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Fu, L., Liu, K., Sun, M., Tian, C., Sun, R., Betanzos, C. M., Tallman, K. A., Porter, N. A., Yang, Y., Guo, D., et al. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000108 · Cited by 75
A Dimethyl-Labeling-Based Strategy for Site-Specifically Quantitative Chemical Proteomics
Yang, F., Gao, J., Che, J., Jia, G., & Wang, C. (2018) · Analytical Chemistry · doi:10.1021/acs.analchem.8b02426 · Cited by 74
Cysteine-reactive probes and their use in chemical proteomics
Hoch, D. G., Abegg, D., & Adibekian, A. (2018) · Chemical Communications · doi:10.1039/c8cc01485j · Cited by 76
Bateman, L. A., Nguyen, T., Roberts, A. M., Miyamoto, D. K., Ku, W.-M., Huffman, T. R., Petri, Y. D., Heslin, M. J., Contreras, C. M., Skibola, C. F., et al. (2017) · Chemical Communications · doi:10.1039/c7cc01480e · Cited by 73
Identifying Functional Cysteine Residues in the Mitochondria
Bak, D. W., Pizzagalli, M. D., & Weerapana, E. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01074 · Cited by 70
Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes
Chen, Y., Craven, G. B., Kamber, R. A., Cuesta, A., Zhersh, S., Moroz, Y. S., Bassik, M. C., & Taunton, J. (2023) · Nature Chemistry · doi:10.1038/s41557-023-01281-3 · Cited by 71
“Fragment-based ligand discovery coupled with quantitative chemical proteomics has been utilized to identify ‘ligandable’ sites in native biological systems 13–17 .”
Pan, S., Ding, A., Li, Y., Sun, Y., Zhan, Y., Ye, Z., Song, N., Peng, B., Li, L., Huang, W., et al. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00056g · Cited by 71
Targeted Covalent Modification Strategies for Drugging the Undruggable Targets
Tamura, T., Kawano, M., & Hamachi, I. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00745 · Cited by 75
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 71
Chemical technology principles for selective bioconjugation of proteins and antibodies
Chauhan, P. S., Ragendu, V., Kumar, M., Molla, R., Mishra, S. D., Basa, S., & Rai, V. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00715d · Cited by 70
Approaches to target tractability assessment – a practical perspective
Brown, K. K., Hann, M. M., Lakdawala, A. S., Santos, R., Thomas, P. J., & Todd, K. (2018) · MedChemComm · doi:10.1039/c7md00633k · Cited by 69
Fragment-to-Lead Medicinal Chemistry Publications in 2017
Mortenson, P. N., Erlanson, D. A., de Esch, I. J. P., Jahnke, W., & Johnson, C. N. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01472 · Cited by 69
Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4–MyD88 Complex
Zaro, B. W., Vinogradova, E. V., Lazar, D. C., Blewett, M. M., Suciu, R. M., Takaya, J., Studer, S., de la Torre, J. C., Casanova, J.-L., Cravatt, B. F., et al. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801627 · Cited by 68
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
Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome
Rao, S., Gurbani, D., Du, G., Everley, R. A., Browne, C. M., Chaikuad, A., Tan, L., Schröder, M., Gondi, S. R., Ficarro, S. B., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.02.021 · Cited by 66
Teng, M., & Gray, N. S. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.020 · Cited by 63
New approaches to target RNA binding proteins
Julio, A. R., & Backus, K. M. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.12.006 · Cited by 69
Self-citationRecent 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 69
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 69
Monitoring Fe–S cluster occupancy across the E. coli proteome using chemoproteomics
Bak, D. W., & Weerapana, E. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01227-9 · Cited by 69
Target identification with quantitative activity based protein profiling (ABPP)
Chen, X., Wong, Y. K., Wang, J., Zhang, J., Lee, Y. M., Shen, H., Lin, Q., & Hua, Z. (2016) · PROTEOMICS · doi:10.1002/pmic.201600212 · Cited by 68
“…was applied on a global level in a recent study by Backus et al., which used isoTOP-ABPP screening of a large constructed library of fragment electrophiles to identify ligandable cysteines in MDA-MB-231 (human breast cancer cell) and Ramos Cell (human B lymphocyte cell) human cancer proteomes [83].”
MethodFICD activity and AMPylation remodelling modulate human neurogenesis
Kielkowski, P., Buchsbaum, I. Y., Kirsch, V. C., Bach, N. C., Drukker, M., Cappello, S., & Sieber, S. A. (2020) · Nature Communications · doi:10.1038/s41467-019-14235-6 · Cited by 65
Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products
Tian, C., Sun, R., Liu, K., Fu, L., Liu, X., Zhou, W., Yang, Y., & Yang, J. H. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.022 · Cited by 62
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
Assigning functionality to cysteines by base editing of cancer dependency genes
Li, H., Ma, T., Remsberg, J. R., Won, S. J., DeMeester, K. E., Njomen, E., Ogasawara, D., Zhao, K. T., Huang, T. P., Lu, B., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01428-w · Cited by 62
“Our identification of a covalent inhibitor targeting C80 in TOE1 that strengthens binding of this protein to spliceosome subcomplexes 36 highlights how integrated base editing and cysteine-directed ABPP data can illuminate essential, ligan-dable sites for allosteric regulation of cancer dependency proteins.”
BackgroundMethodResultInfluentialSelf-citationHeidrich, J., Sperl, L. E., & Boeckler, F. M. (2019) · Frontiers in Chemistry · doi:10.3389/fchem.2019.00009 · Cited by 62
“Fragment libraries can either be unfocused or they can be designed for addressing serine, cysteine (Backus et al., 2016; Craven et al., 2018) and lysine residues by establishing covalent bonds (Kathman and Statsyuk, 2016) with distinct functional groups like boronic acids, epoxides, acrylamides, or N-succinimidyl este…”
BackgroundChemoproteomic-enabled phenotypic screening
Conway, L. P., Li, W., & Parker, C. G. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.012 · Cited by 62
Protein Labeling and Crosslinking by Covalent Aptamers
Tivon, Y., Falcone, G. N., & Deiters, A. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202101174 · Cited by 62
Global profiling of phosphorylation-dependent changes in cysteine reactivity
Kemper, E. K., Zhang, Y., Dix, M. M., & Cravatt, B. F. (2022) · Nature Methods · doi:10.1038/s41592-022-01398-2 · Cited by 61
Self-citationCan Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?
Chatterjee, P., Botello‐Smith, W. M., Zhang, H., Qian, L., Alsamarah, A., Kent, D., Lacroix, J. J., Baudry, M., & Luo, Y. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b08938 · Cited by 63
Nuisance compounds in cellular assays
Dahlin, J. L., Auld, D. S., Rothenaigner, I., Haney, S., Sexton, J. Z., Nissink, J. W. M., Walsh, J. J., Lee, J. A., Strelow, J. M., Willard, F. S., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.021 · Cited by 61
Targeted Protein Degradation through E2 Recruitment
Forte, N., Dovala, D., Hesse, M. J., McKenna, J. M., Tallarico, J. A., Schirle, M., & Nomura, D. K. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00040 · Cited by 63
Activity-based RNA-modifying enzyme probing reveals DUS3L-mediated dihydrouridylation
Dai, W. H., Li, A., Yu, N. J., Nguyen, T., Leach, R. W., Wühr, M., & Kleiner, R. E. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00874-8 · Cited by 56
Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death
Wang, Z., Tan, M., Su, W., Huang, W., Zhang, J., Jia, F., Cao, G., Liu, X., Song, H., Ran, H., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00013 · Cited by 60
Kawano, 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 57
Towards detecting regulatory protein–metabolite interactions
Diether, M., & Sauer, U. (2017) · Current Opinion in Microbiology · doi:10.1016/j.mib.2017.07.006 · Cited by 55
A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review)
He, Y., Zhang, D., Yang, Y., Wang, X., Zhao, X., Zhang, P., Zhu, H., Xu, N., & Liang, S. (2018) · Oncology Reports · doi:10.3892/or.2018.6203 · Cited by 55
The Proteome‐Wide Potential for Reversible Covalency at Cysteine
Senkane, K., Vinogradova, E. V., Suciu, R. M., Crowley, V. M., Zaro, B. W., Bradshaw, J. M., Brameld, K. A., & Cravatt, B. F. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201905829 · Cited by 56
Self-citationTherapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases
Risso, V., Lafont, É., & Gallo, M. L. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04688-x · Cited by 66
Metadata
- Authors
- Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., Wolan, D. W., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Backus, Keriann M.
- Cravatt, Benjamin F.
- ORCID
- Venue
- Nature
- Published
- 2016-06-15
- Volume
- 534
- Issue
- 7608
- Pages
- 570-574
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4919207
- OpenAlex
- W2430132928
- Cited by
- 940
- References
- 43
- Citations by year
- 2026: 109 · 2025: 114 · 2024: 114 · 2023: 134 · 2022: 82 · 2021: 94 · 2020: 87 · 2019: 69 · 2018: 61 · 2017: 54 · 2016: 18
- FWCI
- 31.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (CA-087660, R37CA087660, R01CA087660)
- National Institute of General Medical Sciences (GM069832, GM-090294, GM108208, R01GM090294, F32GM108208, R01GM069832)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- covalent ligands, chemical probes, undruggable proteins, transcription factors, caspase-8, caspase-10, extrinsic apoptotic pathway, T cells, protein function
- MeSH terms
- Cells, Cultured, Cysteine, Drug Evaluation, Preclinical, Enzyme Precursors, Humans, Ligands, Peptide Fragments, T-Lymphocytes, Transcription Factors, Apoptosis, Proteome, Caspase 8, Caspase 10, Small Molecule Libraries
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