Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy
| العنوان: | Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy |
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| المؤلفون: | Ammar Adam, David J. Owen, Justin Cidado, Claire Patterson, Matthew Skinner, Stuart Purbrick, Lorraine Graham, Petar Pop-Damkov, Michael Giannis, Srividya B. Balachander, Francis D. Gibbons, William McCoull, Marianne Ashford, Hill Kathryn Jane, Martin Wild, Eric Gangl, Stephen Fawell, Corinne Reimer, Sean Redmond, Paul D. Kemmitt, Barry R. Davies, Jamal Carlos Saeh, Shenghua Wen, J. Paul Secrist, Alwin Schuller, Edward J. Hennessy, Sonya Gales, Iain Grant, Alexander R. Harmer, Jeremy S. Parker, Brian Kelly |
| المصدر: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Drug, Dendrimers, QH301-705.5, media_common.quotation_subject, bcl-X Protein, Medicine (miscellaneous), Drug development, Antineoplastic Agents, Mice, SCID, Pharmacology, Conjugated system, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Targeted therapies, Dogs, 0302 clinical medicine, Therapeutic index, Neoplasms, Dendrimer, Tumor Cells, Cultured, Animals, Humans, Medicine, Biology (General), Rats, Wistar, media_common, Haematological cancer, business.industry, Xenograft Model Antitumor Assays, Rats, Mice, Inbred C57BL, Therapeutic Index, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Tolerability, 030220 oncology & carcinogenesis, Drug delivery, Female, General Agricultural and Biological Sciences, business, Conjugate |
| الوصف: | Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development. Claire Patterson et al. present the design and development of AZD0466, a drug-dendrimer conjugate, and use preclinical and mathematical models to determine the optimal release rate of the drug from the dendrimer carrier for maximal therapeutic index in terms of anti-tumour efficacy and cardiovascular tolerability. This study identifies this promising dual Bcl-2/Bcl-xL inhibitor for progression to clinical development. |
| تدمد: | 2399-3642 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f928851dba9fe7a39b683d8c12e8a5dTest https://doi.org/10.1038/s42003-020-01631-8Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0f928851dba9fe7a39b683d8c12e8a5d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23993642 |
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