BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies
| العنوان: | BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies |
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| المؤلفون: | Benjamin Bader, Sabine Zitzmann-Kolbe, Carl Friedrich Nising, Ulrich Lücking, Qi Wang, Hartmut Rehwinkel, Florian Bartels, Qiuwen Wang, Markus Berger, Antje Margret Wengner, Lars Wortmann, Dieter Moosmayer, Philipp Buchgraber, Hans Briem, Dominik Mumberg, Knut Eis, Uwe Eberspächer, Stefanie Hammer, Christoph A. Schatz, Gerhard Siemeister, Philip Lienau, Ulf Bömer |
| المصدر: | Journal of Medicinal Chemistry. 64:12723-12737 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | DNA repair, Cell, Antineoplastic Agents, DNA-Activated Protein Kinase, Cell cycle phase, Mice, Phosphatidylinositol 3-Kinases, Structure-Activity Relationship, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Protein kinase A, Cell Proliferation, Molecular Structure, Chemistry, TOR Serine-Threonine Kinases, Drug Synergism, medicine.disease, Xenograft Model Antitumor Assays, In vitro, Rats, medicine.anatomical_structure, Gene Expression Regulation, Ataxia-telangiectasia, Hepatocytes, Cancer research, Molecular Medicine, Drug Therapy, Combination, Homologous recombination, DNA |
| الوصف: | Eukaryotes have evolved two major pathways to repair potentially lethal DNA double-strand breaks. Homologous recombination represents a precise, DNA-template-based mechanism available during the S and G2 cell cycle phase, whereas non-homologous end joining, which requires DNA-dependent protein kinase (DNA-PK), allows for fast, cell cycle-independent but less accurate DNA repair. Here, we report the discovery of BAY-8400, a novel selective inhibitor of DNA-PK. Starting from a triazoloquinoxaline, which had been identified as a hit from a screen for ataxia telangiectasia and Rad3-related protein (ATR) inhibitors with inhibitory activity against ATR, ATM, and DNA-PK, lead optimization efforts focusing on potency and selectivity led to the discovery of BAY-8400. In in vitro studies, BAY-8400 showed synergistic activity of DNA-PK inhibition with DNA damage-inducing targeted alpha therapy. Combination of PSMA-targeted thorium-227 conjugate BAY 2315497 treatment of human prostate tumor-bearing mice with BAY-8400 oral treatment increased antitumor efficacy, as compared to PSMA-targeted thorium-227 conjugate monotherapy. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::239f4b3d5d418e9f129fce60684625c6 https://doi.org/10.1021/acs.jmedchem.1c00762 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....239f4b3d5d418e9f129fce60684625c6 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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