2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2025 Aug 5:292:117641. doi: 10.1016/j.ejmech.2025.117641.
Martina Sukupova 1,  Karolina Knittelova 2,  Elham Parsimehr 3,  David Malinak 4,  Denisa Noskova 2,  Jana Kurcova 5,  Ester Marakova 5,  Zdenek Kratochvil 5,  Vladimir Pekarik 5,  Miroslav Psotka 6,  Jan Korabecny 6,  Ladislav Sivak 5,  Pavel Kulich 7,  Zbynek Heger 8,  Vojtech Adam 5,  Kamil Kuca 9
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-625 00, Brno, Czech Republic.
  • 2 Department of Chemistry, Faculty of Science, University of Hradec Kralove, CZ-500 03, Hradec Kralove, Czech Republic.
  • 3 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic; Department of Genomics and Proteomics, Faculty of Science, Masaryk University, CZ-625 00, Brno, Czech Republic.
  • 4 Department of Chemistry, Faculty of Science, University of Hradec Kralove, CZ-500 03, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, CZ-500 05, Hradec Kralove, Czech Republic. Electronic address: david.malinak@uhk.cz.
  • 5 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic.
  • 6 Biomedical Research Center, University Hospital Hradec Kralove, CZ-500 05, Hradec Kralove, Czech Republic.
  • 7 Veterinary Research Institute, CZ-621 00, Brno, Czech Republic.
  • 8 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic; Center of Advanced Innovation Technologies, Faculty of Materials Science and Technology, VSB - Technical University of Ostrava, CZ-708 00, Ostrava, Czech Republic.
  • 9 Biomedical Research Center, University Hospital Hradec Kralove, CZ-500 05, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, Faculty of Materials Science and Technology, VSB - Technical University of Ostrava, CZ-708 00, Ostrava, Czech Republic; Centre for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, CZ-500 03, Hradec Kralove, Czech Republic. Electronic address: kamil.kuca@fnhk.cz.
PMID: 40286451 DOI: 10.1016/j.ejmech.2025.117641
Abstract

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.

Keywords

Chemosensitization; DNA-Dependent protein kinase; Doxorubicin; Drug delivery; Multitarget inhibition; Phoshphoinositide-3-kinases inhibitors; Resistance.

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