Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
| العنوان: | Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors |
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| المؤلفون: | Shi-Liang Huang, Qi-Kun Yin, Jia-En Wang, Honggen Wang, Ding Li, Chen-Xi Wang, Jia-Heng Tan, Zhi-Shu Huang, Yao-Hao Xu, Yong Rao, Zi-Lin Zhang, Shuo-Bin Chen, Tian-Miao Ou, Jia-Li Tu, Qingjiang Li |
| المصدر: | Journal of Medicinal Chemistry. 63:9752-9772 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Models, Molecular, congenital, hereditary, and neonatal diseases and abnormalities, Protein Conformation, DNA damage, Poly ADP ribose polymerase, Apoptosis, Chemistry Techniques, Synthetic, Poly(ADP-ribose) Polymerase Inhibitors, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Humans, Polymerase, Cell Proliferation, Quinazolinones, 030304 developmental biology, 0303 health sciences, RecQ Helicases, biology, urogenital system, Chemistry, nutritional and metabolic diseases, Helicase, Drug Synergism, Telomere, HCT116 Cells, 0104 chemical sciences, Cell biology, 010404 medicinal & biomolecular chemistry, Bloom syndrome protein, Drug Design, Cancer cell, biology.protein, Molecular Medicine, DNA, DNA Damage |
| الوصف: | DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f21267762456ab0e27c8001c4c005bf https://doi.org/10.1021/acs.jmedchem.0c00917 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....6f21267762456ab0e27c8001c4c005bf |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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