Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function
Open accessAbstract
The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Covalent drug discovery platforms have facilitated expansion of targeted protein degradation by enabling discovery of covalent recruiters against E3 ubiquitin ligases.
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [188]
Since 2019, covalent recruiters have been used to validate a large proportion of E3 ligases harnessed for targeted protein degradation, including RNF114, RNF4, DCAF16, DCAF11, KEAP1 and FEM1B.
“Since 2019, covalent recruiters have been used to validate a large proportion of the E3 ligases that have been harnessed for targeted protein degradation, including RING finger protein 114 (RNF114), RNF4, DDB1 and CUL4-associated factor 16 (DCAF16), DCAF11, KEAP1 and, most recently, fem-1 homologue B (FEM1B)187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [188]
This enabled design of RNF114-based degraders, expanding to other chemotypes.
“This enabled the design of RNF114-based degraders, also expanding to other chemotypes.84,85”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [85]
Additional generic E3 ligases (RNF4, RNF114, KEAP1, FEM1B) have been shown to be exploitable by PROTACs using small-molecule covalent tools to degrade BRD4.
“a few additional ‘generic’ E3 ligases have been shown to be exploitable by PROTACs, using small-molecule covalent tools that specifically recruit the ligases to degrade the prototypical TPD substrate, BRD4; these ligases include ring finger protein 4 (RNF4)132, RNF114 (refs133–135), KEAP1 (refs136,137) and most recently, fem-1 homologue B (FEM1B)138.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [134]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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 · see citing works
Natural products as sources of new drugs from 1981 to 2014
Newman, D. J., & Cragg, G. M. (2016) · Journal of Natural Products · doi:10.1021/acs.jnatprod.5b01055 · Cited by 5,858 · see citing works
Quantitative reactivity profiling predicts functional cysteines in proteomes
Weerapana, E., Wang, C., Simon, G. M., Richter, F., Khare, S., Dillon, M. B. D., Bachovchin, D. A., Mowen, K., Baker, D., & Cravatt, B. F. (2010) · Nature · doi:10.1038/nature09472 · Cited by 1,684 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Proteome-wide covalent ligand discovery in native biological systems
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., et al. (2016) · Nature · doi:10.1038/nature18002 · Cited by 940 · see citing works
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923 · see citing works
Modular PROTAC design for the degradation of oncogenic BCR-ABL
Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618 · see citing works
ProLuCID: An improved SEQUEST-like algorithm with enhanced sensitivity and specificity
Xu, T., Park, S. K., Venable, J. D., Wohlschlegel, J. A., Diedrich, J. K., Cociorva, D., Lu, B., Liao, L., Hewel, J., Han, X., et al. (2015) · Journal of Proteomics · doi:10.1016/j.jprot.2015.07.001 · Cited by 511 · see citing works
Development of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M., & Cravatt, B. F. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0279-5 · Cited by 487 · see citing works
Targeted Degradation of Oncogenic KRAS <sup>G12C</sup> by VHL-Recruiting PROTACs
Bond, M. J., Chu, L., Nalawansha, D. A., Li, K., & Crews, C. M. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00411 · Cited by 450 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
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) · Nature Chemical Biology · doi:10.1038/s41589-019-0304-8 · Cited by 432 · see citing works
Self-citationWard, 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) · ACS Chemical Biology · doi:10.1021/acschembio.8b01083 · Cited by 336 · see citing works
Self-citationA chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles
Wang, C., Weerapana, E., Blewett, M. M., & Cravatt, B. F. (2013) · Nature Methods · doi:10.1038/nmeth.2759 · Cited by 303 · see citing works
Bachovchin, D. A., Ji, T., Li, W., Simon, G. M., Blankman, J. L., Adibekian, A., Hoover, H. S., Niessen, S., & Cravatt, B. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011663107 · Cited by 275 · see citing works
Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
Burslem, G. M., Schultz, A. R., Bondeson, D. P., Eide, C. A., Savage Stevens, S. L., Druker, B. J., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1236 · Cited by 212 · see citing works
Targeted Protein Degradation by Small Molecules
Bondeson, D. P., & Crews, C. M. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103507 · Cited by 207 · see citing works
Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo
Jessani, N., Humphrey, M., McDonald, W. H., Niessen, S., Masuda, K. R., Gangadharan, B., Yates, J. R., Mueller, B. M., & Cravatt, B. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404727101 · Cited by 181 · see citing works
Ottis, P., Palladino, C., Thienger, P., Britschgi, A., Heichinger, C., Berrera, M., Julien-Laferrière, A., Roudnicky, F., Kam‐Thong, T., Bischoff, J. R., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00525 · Cited by 153 · see citing works
Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products
Grossman, E. A., Ward, C. C., Spradlin, J. N., Bateman, L. A., Huffman, T. R., Miyamoto, D. K., Kleinman, J. I., & Nomura, D. K. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.013 · Cited by 124 · see citing works
Self-citationA Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
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. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118 · see citing works
Self-citationEnantioselective Phase‐Transfer Catalysis: Synthesis of Pyrazolines
Mahé, O., Dez, I., Levacher, V., et al. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.201002485 · Cited by 91 · see citing works
Han, J., Yl, K., Lee, K.-W., Her, N.-G., Ha, T.-K., Yoon, S., Jeong, S.-I., Lee, J.-H., Kang, M. J., Lee, M.-G., et al. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.33 · Cited by 73 · see citing works
Target Identification of Bioactive Covalently Acting Natural Products
Nomura, D. K., & Maimone, T. J. (2018) · Current topics in microbiology and immunology · doi:10.1007/82_2018_121 · Cited by 43 · see citing works
Self-citationThomas, J. R., Brittain, S. M., Lipps, J., Llamas, L., Jain, R. K., & Schirle, M. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7201-2_1 · Cited by 29 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Xu T, Park SK, Venable JD, Wohlschlegel JA, Diedrich JK, Cociorva D, Lu B, Liao L, Hewel J, Han X, (2015b). ProLuCID: An improved SEQUEST-like algorithm with enhanced sensitivity and specificity. J Proteomics 129, 16– 24. 26171723 PMC4630125
Cited by
Sorted by citations
PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
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
Self-citationDeubiquitinase-targeting chimeras for targeted protein stabilization
Henning, N. J., Boike, L., Spradlin, J. N., Ward, C. C., Liu, G., Zhang, E., Belcher, B. P., Brittain, S. M., Hesse, M. J., Dovala, D., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00971-2 · Cited by 344 · see citing works
Self-citationChemistries 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
Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
Henning, N. J., Manford, A. G., Spradlin, J. N., Brittain, S. M., Zhang, E., McKenna, J. M., Tallarico, J. A., Schirle, M., Rape, M., & Nomura, D. K. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03980 · Cited by 221 · 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
Self-citationLigandability of E3 Ligases for Targeted Protein Degradation Applications
Belcher, B. P., Ward, C. C., & Nomura, D. K. (2023) · Biochemistry · doi:10.1021/acs.biochem.1c00464 · Cited by 132 · see citing works
Self-citationPROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms
Rodriguez-Rivera, F. P., & Levi, S. M. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00389 · Cited by 30 · see citing works
Adhikari, B., Schneider, K., Diebold, M., Sotriffer, C., & Wolf, E. (2024) · eLife · doi:10.7554/elife.98450.3 · Cited by 6 · see citing works
- Authors
- Luo, M., Spradlin, J. N., Boike, L., Tong, B., Brittain, S. M., McKenna, J. M., Tallarico, J. A., Schirle, M., Maimone, T. J., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Innovative Genomics Institute (US)
- Corresponding author
- Maimone, Thomas J.
- Nomura, Daniel K.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 28
- Issue
- 4
- Pages
- 559-566.e15
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC8052289
- OpenAlex
- W3123549562
- Cited by
- 186
- References
- 26
- Citations by year
- 2026: 29 · 2025: 34 · 2024: 50 · 2023: 27 · 2022: 34 · 2021: 12
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Mark Foundation For Cancer Research
- National Cancer Institute
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- RNF114, targeted protein degradation, PROTACs, nimbolide, covalent ligands, BRD4 degradation, activity-based protein profiling, chemoproteomics
- MeSH terms
- Biological Products, Humans, Molecular Structure, Proteomics, Ubiquitin-Protein Ligases, Ubiquitination
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
