Antibody–PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4
Open accessAbstract
Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.
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Antibody-PROTAC conjugates can selectively degrade proteins of interest in targeted cells or tissues.
“These Ab-PROTACs can selectively degrade POIs in targeted cells/tissues [38–40].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [38]
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Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212 · 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
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
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
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056 · 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
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
Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling
Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G., & Pavletich, N. P. (2002) · Science · doi:10.1126/science.1073440 · Cited by 765 · see citing works
Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15
Han, T., Goralski, M., Gaskill, N., Capota, E., Kim, J., Ting, T. C., Xie, Y., Williams, N. S., & Nijhawan, D. (2017) · Science · doi:10.1126/science.aal3755 · Cited by 762 · see citing works
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751 · see citing works
BET domain co-regulators in obesity, inflammation and cancer
Belkina, A. C., & Denis, G. V. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3256 · Cited by 727 · see citing works
Targeted protein degradation: elements of PROTAC design
Paiva, S.-L., & Crews, C. M. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.02.022 · Cited by 586 · see citing works
Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer
Lambert, J. M., & Chari, R. V. J. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500766w · Cited by 545 · see citing works
Austin, C. D., Mazière, A. M. G. L. D., Pisacane, P. I., van Dijk, S., Eigenbrot, C. W., Sliwkowski, M. X., Klumperman, J., & Scheller, R. H. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-07-0591 · Cited by 498 · see citing works
Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?
Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · see citing works
Antibody Conjugate Therapeutics: Challenges and Potential
Teicher, B. A., & Chari, R. V. J. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1417 · Cited by 427 · see citing works
Delineating the role of cooperativity in the design of potent PROTACs for BTK
Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803662115 · Cited by 419 · see citing works
Han, X., Wang, C., Qin, C., Xiang, W., Fernández‐Salas, E., Yang, C., Wang, M., Zhao, L., Xu, T., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01631 · Cited by 404 · see citing works
Selective degradation of splicing factor CAPERα by anticancer sulfonamides
Uehara, T., Minoshima, Y., Sagane, K., Sugi, N. H., Mitsuhashi, K. O., Yamamoto, N., Kamiyama, H., Takahashi, K., Kotake, Y., Uesugi, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2363 · Cited by 396 · see citing works
Amiri‐Kordestani, L., Blumenthal, G. M., Xu, Q., Zhang, L., Tang, S. W., Ha, L., Weinberg, W. C., Chi, B., Candau-Chacon, R., Hughes, P., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0012 · Cited by 352 · see citing works
Salami, J., Alabi, S., Willard, R. R., Vitale, N. J., Wang, J., Dong, H., Jin, M., McDonnell, D. P., Crew, A. P., Neklesa, T. K., et al. (2018) · Communications Biology · doi:10.1038/s42003-018-0105-8 · Cited by 349 · see citing works
Antibody–Drug Conjugates for Cancer Treatment
Lambert, J. M., & Berkenblit, A. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-061516-121357 · Cited by 314 · see citing works
Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01572 · Cited by 286 · see citing works
Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates
Mahalingaiah, P. K., Ciurlionis, R., Durbin, K. R., Yeager, R. L., Philip, B. K., Bawa, B., Mantena, S. R., Enright, B. P., Liguori, M. J., & Van Vleet, T. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.04.008 · Cited by 286 · see citing works
Crew, A. P., Raina, K., Dong, H., Qian, Y., Wang, J., Vigil, D., Serebrenik, Y. V., Hamman, B. D., Morgan, A., Ferraro, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00635 · Cited by 257 · see citing works
Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy
Ottis, P., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01068 · Cited by 227 · see citing works
Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
Faust, T. B., Yoon, H., Nowak, R. P., Donovan, K. A., Li, Z., Cai, Q., Eleuteri, N. A., Zhang, T., Gray, N. S., & Fischer, E. S. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0378-3 · Cited by 218 · see citing works
Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity
Pillow, T. H., Adhikari, P., Blake, R. A., Chen, J., Del Rosario, G., Deshmukh, G., Figueroa, I., Gascoigne, K. E., Kamath, A. V., Kaufman, S., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.201900497 · Cited by 216 · see citing works
Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule
Zhao, Q., Lan, T., Su, S., & Rao, Y. (2018) · Chemical Communications · doi:10.1039/c8cc07813k · Cited by 185 · see citing works
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) · Structure · doi:10.1016/j.str.2019.10.005 · Cited by 181 · see citing works
Burslem, G. M., Song, J., Chen, X., Hines, J., & Crews, C. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b10320 · Cited by 176 · see citing works
PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer
Zhao, B., & Burgess, K. (2019) · Chemical Communications · doi:10.1039/c9cc00163h · Cited by 130 · see citing works
Nunes, J. P. M., Morais, M., Vassileva, V., et al. (2015) · Chemical Communications · doi:10.1039/c5cc03557k · Cited by 121 · see citing works
Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
Dragovich, P. S., Adhikari, P., Blake, R. A., Blaquiere, N., Chen, J., Cheng, Y.-X., den Besten, W., Han, J., Hartman, S. J., He, J., et al. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126907 · Cited by 120 · see citing works
Quantitative Analysis of Endocytosis and Turnover of Epidermal Growth Factor (EGF) and EGF Receptor
Sorkin, A. D., & Duex, J. E. (2010) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb1514s46 · Cited by 97 · see citing works
Robinson, E., Nunes, J. P. M., Vassileva, V., et al. (2017) · RSC Advances · doi:10.1039/c7ra00788d · Cited by 78 · see citing works
Morais, M., Nunes, J. P. M., Karu, K., et al. (2017) · Organic & Biomolecular Chemistry · doi:10.1039/c7ob00220c · Cited by 72 · see citing works
Homogeneous antibody-drug conjugates via site-selective disulfide bridging
Forte, N., Chudasama, V., & Baker, J. R. (2018) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.09.004 · Cited by 66 · see citing works
Self-citationTargeting bromodomain and extraterminal proteins in breast cancer
Sahni, J. M., & Keri, R. A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.11.015 · Cited by 60 · see citing works
Arvinas’s PROTACs pass first safety and PK analysis
Mullard, A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/d41573-019-00188-4 · Cited by 43 · see citing works
Small molecule-mediated protein knockdown as a new approach to drug discovery
Tinworth, C. P., Lithgow, H., & Churcher, I. (2016) · MedChemComm · doi:10.1039/c6md00347h · Cited by 32 · see citing works
Hazin, J., Moldenhauer, G., Altevogt, P., et al. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.04.024 · Cited by 16 · see citing works
Casalini, P., Caldera, M., Canevari, S., et al. (1993) · Cancer Immunology Immunotherapy · doi:10.1007/bf01516942 · Cited by 12 · see citing works
Isa, M., Asanuma, D., Namiki, S., et al. (2014) · ACS Chemical Biology · doi:10.1021/cb500654q · Cited by 10 · see citing works
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Tsuchikama, K., Anami, Y., Ha, S. Y. Y., & Yamazaki, C. M. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00850-2 · Cited by 659 · see citing works
Antibody–drug conjugates: Recent advances in payloads
Wang, Z., Li, H., Gou, L., Li, W., & Wang, Y. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.06.015 · Cited by 264 · see citing works
PROTACs: 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
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
Hu, Z., & Crews, C. M. (2022) · ChemBioChem · doi:10.1002/cbic.202100270 · Cited by 231 · see citing works
Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Chen, J., Corr, N., dela Cruz-Chuh, J., Del Rosario, G., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01846 · Cited by 174 · see citing works
Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Bhakta, S., Blaquiere, N., Chen, J., dela Cruz-Chuh, J., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01845 · Cited by 152 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Targeted protein modification as a paradigm shift in drug discovery
Amirian, R., Azadi Badrbani, M., Izadi, Z., Samadian, H., Bahrami, G., Sarvari, S., Abdolmaleki, S., Nabavi, S. M., Derakhshankhah, H., & Jaymand, M. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115765 · Cited by 18 · see citing works
- Authors
- Maneiro, M., Forte, N., Shchepinova, M. M., Kounde, C. S., Chudasama, V., Baker, J. R., & Tate, E. W.
- Affiliations
- Imperial College London (GB)
- University College London (GB)
- Corresponding author
- Tate, Edward W.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-04-27
- Volume
- 15
- Issue
- 6
- Pages
- 1306-1312
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC7309268
- OpenAlex
- W3019413018
- Cited by
- 350
- References
- 44
- Citations by year
- 2026: 69 · 2025: 60 · 2024: 64 · 2023: 67 · 2022: 49 · 2021: 29 · 2020: 11 · 2014: 1
- FWCI
- 12.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Chemical Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline (NA)
- Engineering and Physical Sciences Research Council (EP/R034621/1, EP/R512540/1)
- Xunta de Galicia (NA)
- 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
- PROTACs, targeted protein degradation, BRD4, HER2-positive breast cancer, trastuzumab, lysosomal trafficking, E3 ubiquitin ligase, protein internalization
- MeSH terms
- Trastuzumab, Antineoplastic Agents, Immunological, Bromodomain Containing Proteins, Cell Line, Humans, Transcription Factors, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Immunoconjugates, Cell Cycle Proteins, Cell Line, Tumor, Proteolysis, MCF-7 Cells
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