Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.
Maria V Zapevalova, Ekaterina S Shchegravina, Irina P Fonareva, Diana I Salnikova, Danila V Sorokin, Alexander M Scherbakov, Alexander A Maleev, Stanislav K Ignatov, Ivan D Grishin, Alexander N Kuimov, Maryia V Konovalova, Elena V Svirshchevskaya, Alexey Yu Fedorov
Author Information
Maria V Zapevalova: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
Ekaterina S Shchegravina: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia. ORCID
Irina P Fonareva: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
Diana I Salnikova: Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115522 Moscow, Russia. ORCID
Danila V Sorokin: Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115522 Moscow, Russia.
Alexander M Scherbakov: Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115522 Moscow, Russia. ORCID
Alexander A Maleev: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
Stanislav K Ignatov: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
Ivan D Grishin: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
Alexander N Kuimov: A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia.
Maryia V Konovalova: Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya 16/10, 117997 Moscow, Russia. ORCID
Elena V Svirshchevskaya: Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
Alexey Yu Fedorov: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.
A (series) range of potential dimorpholinoquinazoline-based inhibitors of the was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound inhibited the phosphorylation of Akt, mTOR, and S6K at 125-250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 50 µM and of 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for . In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib () by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.
