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
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40286451
DOI
10.1016/j.ejmech.2025.117641
PII: S0223-5234(25)00406-4
Knihovny.cz E-zdroje
- Klíčová slova
- Chemosensitization, DNA-Dependent protein kinase, Doxorubicin, Drug delivery, Multitarget inhibition, Phoshphoinositide-3-kinases inhibitors, Resistance,
- MeSH
- chemorezistence * účinky léků MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy * farmakologie MeSH
- inhibitory proteinkinas * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- mnohočetná léková rezistence * účinky léků MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- P-glykoprotein * antagonisté a inhibitory metabolismus MeSH
- proliferace buněk účinky léků MeSH
- proteinkinasa aktivovaná DNA * antagonisté a inhibitory metabolismus MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fosfatidylinositol-3-kinasy MeSH
- inhibitory fosfoinositid-3-kinasy * MeSH
- inhibitory proteinkinas * MeSH
- P-glykoprotein * MeSH
- proteinkinasa aktivovaná DNA * MeSH
- protinádorové látky * 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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