7B7S

CDK2/cyclin A2 in complex with 3H-pyrazolo[4,3-f]quinoline-based derivative HSD1368

7B7S の概要

• エントリーDOI: 10.2210/pdb7b7s/pdb
• 分子名称: 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)
• 機能のキーワード: cyclin-dependent kinase, flt3, acute myeloid leukemia, inhibition, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 128646.66

構造登録者

Djukic, S.,Skerlova, J.,Rezacova, P. (登録日: 2020-12-11, 公開日: 2021-08-04, 最終更新日: 2024-11-06)

主引用文献

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

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: 34288692
DOI: 10.1021/acs.jmedchem.1c00330

実験手法

X-RAY DIFFRACTION (2.54 Å)