Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
| Autor: | Mingtao He, Chun Sing Li, Yongxin Zhao, Deepak Sampath, Leanna Staben, Ingrid E. Wertz, Hao Zhou, Rebecca K. Rowntree, Ellen Ingalla, Xinxin Wang, Richard Zang, Ying Lu, Qi Liu, Jiawei Lu, Gail Lewis Phillips, Binqing Wei, Fanwei Meng, Nicole Blaquiere, Yun-Xing Cheng, Steven T. Staben, Keyang Xu, Jinping Han, Tommy Lai, Kaishan Peng, Kunpeng Wan, Peter S. Dragovich, Lingyao Meng, Tracy Kleinheinz, Jinhua Chen, Amrita V. Kamath, John S. Wai, Carl Ng, Pragya Adhikari, Steven J. Hartman, Jianfeng Xin, Jintang He, Douglas D. Leipold, Thomas H. Pillow, Donglu Zhang, Hui Yao, Jack Sadowsky, Robert A. Blake, Willem den Besten |
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| Rok vydání: | 2019 |
| Předmět: |
Immunoconjugates
medicine.drug_class Receptor ErbB-2 Clinical Biochemistry Pharmaceutical Science Estrogen receptor Antineoplastic Agents Monoclonal antibody 01 natural sciences Biochemistry In vivo Drug Discovery medicine Humans Molecular Biology Drug Carriers 010405 organic chemistry Chemistry Organic Chemistry Estrogen Receptor alpha Antibodies Monoclonal Fusion protein 0104 chemical sciences 010404 medicinal & biomolecular chemistry Drug Design Drug delivery Proteolysis MCF-7 Cells Molecular Medicine Estrogen receptor alpha Linker Intracellular |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(4) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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