N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides as novel multi-PI3K/DNA-PK/P-gp inhibitors for efficient chemosensitization and MDR alleviation
Language English Country France Media print-electronic
Document type Journal Article
PubMed
40286451
DOI
10.1016/j.ejmech.2025.117641
PII: S0223-5234(25)00406-4
Knihovny.cz E-resources
- Keywords
- Chemosensitization, DNA-Dependent protein kinase, Doxorubicin, Drug delivery, Multitarget inhibition, Phoshphoinositide-3-kinases inhibitors, Resistance,
- MeSH
- Drug Resistance, Neoplasm * drug effects MeSH
- Phosphatidylinositol 3-Kinases metabolism MeSH
- Phosphoinositide-3 Kinase Inhibitors * pharmacology MeSH
- Protein Kinase Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Drug Resistance, Multiple * drug effects MeSH
- Molecular Structure MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 * antagonists & inhibitors metabolism MeSH
- Cell Proliferation drug effects MeSH
- DNA-Activated Protein Kinase * antagonists & inhibitors metabolism MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Phosphatidylinositol 3-Kinases MeSH
- Phosphoinositide-3 Kinase Inhibitors * MeSH
- Protein Kinase Inhibitors * MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 * MeSH
- DNA-Activated Protein Kinase * MeSH
- Antineoplastic Agents * MeSH
PI3K signaling pathway is crucial for a plethora of cellular processes and is extensively linked with tumorigenesis and chemo-/radioresistance. Although a number of small molecule inhibitors have been synthesized to control PI3K-mediated signaling, only a limited clinical success has been reached. Thus, the search for novel promising candidates is still ongoing. Herein, we present a novel series of N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides designed to simultaneously inhibit PI3K and DNA-PK activity. Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239). Through an array of biological experiments, we selected two most promising compounds, 2 and 6. While in cell-free conditions, 6 acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, 2 performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin. This was plausibly due to its improved ability to accumulate in nuclei as evidenced by confocal analyses. Importantly, using P-gp overexpressing CT26 cells, we found that 2 is an efficient inhibitor of multidrug resistance (MDR) able to down-regulate expression of mRNA encoding MDR-driving proteins ABCB1A, ABCB1B and ABCC1. We also demonstrate that 2 can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance.
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