Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Open accessAbstract
Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
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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 [137]
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Cites
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262 · see citing works
Self-citationBET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.017 · Cited by 2,820 · see citing works
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,262 · see citing works
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · 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
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., & Yamamoto, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.8.2887-2900.2006 · Cited by 759 · see citing works
BRD4 and Cancer: going beyond transcriptional regulation
Donati, B., Lorenzini, E., & Ciarrocchi, A. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0915-9 · Cited by 724 · see citing works
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 671 · see citing works
Self-citationE3 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
Hines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2918 · Cited by 348 · see citing works
Davies, T. G., Wixted, W. E., Coyle, J. E., Griffiths-Jones, C., Hearn, K., McMenamin, R., Norton, D., Rich, S. J., Richardson, C., Saxty, G., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00228 · Cited by 322 · see citing works
Lu, M., Liu, T., Jiao, Q., Ji, J., Tao, M., Liu, Y., You, Q., & Jiang, Z. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.01.063 · Cited by 310 · see citing works
Genschik, P., Sumara, I., & Lechner, E. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.173 · Cited by 278 · see citing works
Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO
Cleasby, A., Yon, J. R., Day, P. J., Richardson, C. J., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R. A. E., Concha, N. O., Kerns, J. K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098896 · Cited by 263 · see citing works
Discovery of a first-in-class EZH2 selective degrader
Ma, A., Στρατικόπουλος, Η., Park, K., Wei, J., Martin, T. C., Yang, X., Schwarz, M. C., Leshchenko, V. V., Rialdi, A., Dale, B., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0421-4 · Cited by 240 · see citing works
Self-citationHonda, T., Rounds, B. V., Gribble, G. W., Suh, N., Wang, Y., & Sporn, M. B. (1998) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(98)00479-x · Cited by 204 · see citing works
Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Bai, L., Zhou, B., Yang, C.-Y., Ji, J., McEachern, D., Przybranowski, S., Jiang, H., Hu, J., Xu, F., Zhao, Y., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2622 · Cited by 199 · see citing works
Opposing Functions of BRD4 Isoforms in Breast Cancer
Wu, S.-Y., Lee, C.-F., Lai, H., Yu, C., Lee, J., Zuo, H., Tsai, S. Y., Tsai, M., Ge, K., Wan, Y., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.034 · Cited by 195 · see citing works
Roles of the BRD4 short isoform in phase separation and active gene transcription
Han, X., Yu, D., Gu, R., Jia, Y., Wang, Q., Jaganathan, A., Yang, X., Yu, M., Babault, N., Zhao, C., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0394-8 · Cited by 172 · see citing works
Chaidos, A., Caputo, V. S., & Karadimitris, A. (2015) · Therapeutic Advances in Hematology · doi:10.1177/2040620715576662 · Cited by 166 · see citing works
Bardoxolone conjugation enables targeted protein degradation of BRD4
Tong, B., Luo, M., Xie, Y., Spradlin, J. N., Tallarico, J. A., McKenna, J. M., Schirle, M., Maimone, T. J., & Nomura, D. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-72491-9 · Cited by 149 · see citing works
Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction
Lee, S., & Hu, L. (2020) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02539-y · Cited by 136 · see citing works
Pallesen, J. S., Tran, K. T., & Bach, A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00358 · Cited by 111 · see citing works
Heightman, T. D., Callahan, J. F., Chiarparin, E., Coyle, J. E., Griffiths-Jones, C., Lakdawala, A. S., McMenamin, R. L., Mortenson, P. N., Norton, D., Peakman, T. M., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00279 · Cited by 100 · see citing works
Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR
Yore, M. M., Kettenbach, A. N., Sporn, M. B., Gerber, S. A., & Liby, K. T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022862 · Cited by 99 · see citing works
CDDO-imidazolide Targets Multiple Amino Acid Residues on the Nrf2 Adaptor, Keap1
Meng, X., Waddington, J. C., Tailor, A., Lister, A., Hamlett, J., Berry, N. G., Park, B. K., & Sporn, M. B. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01088 · Cited by 50 · see citing works
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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
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
Self-citationPROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00999-9 · Cited by 283 · see citing works
Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets
Xiong, Y., Zhong, Y., Yim, H., Yang, X., Park, K.-S., Xie, L., Poulikakos, P. I., Han, X., Xiong, Y., Chen, X., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c09255 · Cited by 154 · see citing works
Self-citationAcetylation targeting chimera enables acetylation of the tumor suppressor p53
Kabir, M., Sun, N., Hu, X., Martin, T. C., Yi, J., Zhong, Y., Xiong, Y., Kaniskan, H. Ü., Gu, W., Parsons, R., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c04640 · Cited by 65 · see citing works
Self-citationCuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
Dixon, T., MacPherson, D., Mostofian, B., Dauzhenka, T., Lotz, S., McGee, D., Shechter, S., Shrestha, U. R., Wiewiora, R., McDargh, Z. A., et al. (2021) · doi:10.1101/2021.09.26.461830 · Cited by 7 · 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
- Wei, J., Meng, F., Park, K.-S., Yim, H., Velez, J., Kumar, P., Wang, L., Xie, L., Chen, H., Shen, Y., Teichman, E., Li, D., Wang, G. G., Chen, X., Kaniskan, H. Ü., & Jin, J.
- Affiliations
- Tisch Cancer Institute (US)
- University of North Carolina at Chapel Hill (US)
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
- Corresponding author
- Jin, Jian
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-09-14
- Volume
- 143
- Issue
- 37
- Pages
- 15073-15083
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC8480205
- OpenAlex
- W3200646433
- Cited by
- 154
- References
- 29
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 33 · 2023: 30 · 2022: 29 · 2021: 4 · 2014: 1
- FWCI
- 7.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA196521, R01CA218600, R01CA230854, R01CA260666, R01GM122749)
- National Institute of General Medical Sciences (R01GM122749)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- Keap1, PROTACs, targeted protein degradation, E3 ubiquitin ligase, ubiquitin-proteasome system, BRD4, BRD3, BRD2, cereblon, antiproliferative activity, breast cancer cells
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Antineoplastic Agents, Heterocyclic Compounds, 3-Ring, Humans, Models, Molecular, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Proteolysis, Triple Negative Breast Neoplasms
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