-
Something wrong with this record ?
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
M. Sukupova, K. Knittelova, E. Parsimehr, D. Malinak, D. Noskova, J. Kurcova, E. Marakova, Z. Kratochvil, V. Pekarik, M. Psotka, J. Korabecny, L. Sivak, P. Kulich, Z. Heger, V. Adam, K. Kuca
Language English Country France
Document type Journal Article
- 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
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.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc25015116
- 003
- CZ-PrNML
- 005
- 20250731090754.0
- 007
- ta
- 008
- 250708e20250415fr f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ejmech.2025.117641 $2 doi
- 035 __
- $a (PubMed)40286451
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a fr
- 100 1_
- $a Sukupova, Martina $u 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
- 245 10
- $a 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 / $c M. Sukupova, K. Knittelova, E. Parsimehr, D. Malinak, D. Noskova, J. Kurcova, E. Marakova, Z. Kratochvil, V. Pekarik, M. Psotka, J. Korabecny, L. Sivak, P. Kulich, Z. Heger, V. Adam, K. Kuca
- 520 9_
- $a 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.
- 650 _2
- $a lidé $7 D006801
- 650 12
- $a proteinkinasa aktivovaná DNA $x antagonisté a inhibitory $x metabolismus $7 D051747
- 650 12
- $a chemorezistence $x účinky léků $7 D019008
- 650 12
- $a protinádorové látky $x farmakologie $x chemie $x chemická syntéza $7 D000970
- 650 12
- $a inhibitory fosfoinositid-3-kinasy $x farmakologie $7 D000081082
- 650 _2
- $a vztahy mezi strukturou a aktivitou $7 D013329
- 650 _2
- $a fosfatidylinositol-3-kinasy $x metabolismus $7 D019869
- 650 _2
- $a molekulární struktura $7 D015394
- 650 12
- $a inhibitory proteinkinas $x farmakologie $x chemie $x chemická syntéza $7 D047428
- 650 12
- $a P-glykoprotein $x antagonisté a inhibitory $x metabolismus $7 D020168
- 650 12
- $a mnohočetná léková rezistence $x účinky léků $7 D018432
- 650 _2
- $a vztah mezi dávkou a účinkem léčiva $7 D004305
- 650 _2
- $a screeningové testy protinádorových léčiv $7 D004354
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a proliferace buněk $x účinky léků $7 D049109
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a myši $7 D051379
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Knittelova, Karolina $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, CZ-500 03, Hradec Kralove, Czech Republic
- 700 1_
- $a Parsimehr, Elham $u 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
- 700 1_
- $a Malinak, David $u 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
- 700 1_
- $a Noskova, Denisa $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, CZ-500 03, Hradec Kralove, Czech Republic
- 700 1_
- $a Kurcova, Jana $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Marakova, Ester $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Kratochvil, Zdenek $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Pekarik, Vladimir $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Psotka, Miroslav $u Biomedical Research Center, University Hospital Hradec Kralove, CZ-500 05, Hradec Kralove, Czech Republic
- 700 1_
- $a Korabecny, Jan $u Biomedical Research Center, University Hospital Hradec Kralove, CZ-500 05, Hradec Kralove, Czech Republic
- 700 1_
- $a Sivak, Ladislav $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Kulich, Pavel $u Veterinary Research Institute, CZ-621 00, Brno, Czech Republic
- 700 1_
- $a Heger, Zbynek $u 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
- 700 1_
- $a Adam, Vojtech $u Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00, Brno, Czech Republic
- 700 1_
- $a Kuca, Kamil $u 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
- 773 0_
- $w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 292 (20250415), s. 117641
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/40286451 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20250708 $b ABA008
- 991 __
- $a 20250731090748 $b ABA008
- 999 __
- $a ok $b bmc $g 2366159 $s 1252241
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2025 $b 292 $c - $d 117641 $e 20250415 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628
- LZP __
- $a Pubmed-20250708
