Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
Abstract
Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.
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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 [40]
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- Authors
- 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., He, M., Rei Ingalla, E., Kamath, A. V., Kleinheinz, T., Lai, T., Leipold, D. D., Li, C. S., Liu, Q., Lu, J., Lu, Y., Meng, F., Meng, L., Ng, C., Peng, K., Lewis Phillips, G., Pillow, T. H., Rowntree, R. K., Sadowsky, J. D., Sampath, D., Staben, L., Staben, S. T., Wai, J., Wan, K., Wang, X., Wei, B., Wertz, I. E., Xin, J., Xu, K., Yao, H., Zang, R., Zhang, D., Zhou, H., & Zhao, Y.
- Affiliations
- Genentech (US)
- WuXi AppTec (China) (CN)
- Pharmaron (China) (CN)
- Corresponding author
- Dragovich, Peter S.
- ORCID
- Dragovich, Peter S.
- Adhikari, Pragya
- Chen, Jinhua
- Hartman, Steven J.
- He, Jintang
- He, Mingtao
- Leipold, Douglas D.
- Lu, Jiawei
- Lu, Ying
- Meng, Fanwei
- Ng, Carl
- Pillow, Thomas H.
- Rowntree, Rebecca K.
- Sadowsky, Jack D.
- Sampath, Deepak
- Staben, Steven T.
- Wang, Xinxin
- Wei, BinQing
- Wertz, Ingrid E.
- Xu, Keyang
- Yao, Hui
- Zang, Richard
- Zhang, Donglu
- Zhou, Hao
- Zhao, Yongxin
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 4
- Pages
- 126907
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2994869094
- Cited by
- 120
- References
- 54
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 21 · 2023: 28 · 2022: 23 · 2021: 11 · 2020: 8
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, estrogen receptor alpha, antibody-drug conjugates, antibody conjugation, E3 ubiquitin ligase, in vivo stability, oral bioavailability
- MeSH terms
- Antibodies, Monoclonal, Antineoplastic Agents, Drug Carriers, Humans, Drug Design, Erb-b2 Receptor Tyrosine Kinases, Immunoconjugates, Estrogen Receptor alpha, Proteolysis, MCF-7 Cells
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