7B7S
CDK2/cyclin A2 in complex with 3H-pyrazolo[4,3-f]quinoline-based derivative HSD1368
Summary for 7B7S
| Entry DOI | 10.2210/pdb7b7s/pdb |
| Descriptor | Cyclin-dependent kinase 2, Cyclin-A2, 7-(3-(trifluoromethyl)-1H-pyrazol-4yl)-3,8,10,11-tetrahydropyrazolo[4,3-f]thiopyrano[3,4-c]quinoline 9-oxide, ... (7 entities in total) |
| Functional Keywords | cyclin-dependent kinase, flt3, acute myeloid leukemia, inhibition, cell cycle |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 128646.66 |
| Authors | Djukic, S.,Skerlova, J.,Rezacova, P. (deposition date: 2020-12-11, release date: 2021-08-04, Last modification date: 2024-11-06) |
| Primary citation | Dayal, N.,Reznickova, E.,Hernandez, D.E.,Perina, M.,Torregrosa-Allen, S.,Elzey, B.D.,Skerlova, J.,Ajani, H.,Djukic, S.,Vojackova, V.,Lepsik, M.,Rezacova, P.,Krystof, V.,Jorda, R.,Sintim, H.O. 3 H -Pyrazolo[4,3- f ]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo. J.Med.Chem., 64:10981-10996, 2021 Cited by PubMed Abstract: The 3-pyrazolo[4,3-]quinoline moiety has been recently shown to be a privileged kinase inhibitor core with potent activities against acute myeloid leukemia (AML) cell lines in vitro. Herein, various 3-pyrazolo[4,3-]quinoline-containing compounds were rapidly assembled via the Doebner-Povarov multicomponent reaction from the readily available 5-aminoindazole, ketones, and heteroaromatic aldehydes in good yields. The most active compounds potently inhibit the recombinant FLT3 kinase and its mutant forms with nanomolar IC values. Docking studies with the FLT3 kinase showed a type I binding mode, where the 3-pyrazolo group interacts with Cys694 in the hinge region. The compounds blocked the proliferation of AML cell lines harboring oncogenic FLT3-ITD mutations with remarkable IC values, which were comparable to the approved FLT3 inhibitor quizartinib. The compounds also inhibited the growth of leukemia in a mouse-disseminated AML model, and hence, the novel 3-pyrazolo[4,3-]quinoline-containing kinase inhibitors are potential lead compounds to develop into anticancer agents, especially for kinase-driven cancers. PubMed: 34288692DOI: 10.1021/acs.jmedchem.1c00330 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.54 Å) |
Structure validation
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