3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

0545107 - ÚOCHB 2022 RIV US eng J - Journal Article
Dayal, N. - Řezníčková, E. - Hernandez, D. E. - Peřina, M. - Torregrosa-Allen, S. - Elzey, B. D. - Škerlová, Jana - Ajani, Haresh - Djukic, Stefan - Vojáčková, V. - Lepšík, Martin - Řezáčová, Pavlína - Kryštof, V. - Jorda, R. - Sintim, H. O.
3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo.
Journal of Medicinal Chemistry. Roč. 64, č. 15 (2021), s. 10981-10996. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Research Infrastructure: e-INFRA CZ - 90140
Institutional support: RVO:61388963
Keywords : discovery * FLT3 * cell proliferation
OECD category: Medicinal chemistry
Impact factor: 8.039, year: 2021
Method of publishing: Limited access
https://doi.org/10.1021/acs.jmedchem.1c00330

The 3H-pyrazolo[4,3-f]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 3H-pyrazolo[4,3-f]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 IC50 values. Docking studies with the FLT3 kinase showed a type I binding mode, where the 3H-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 IC50 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 3H-pyrazolo[4,3-f]quinoline-containing kinase inhibitors are potential lead compounds to develop into anticancer agents, especially for kinase-driven cancers.
Permanent Link: http://hdl.handle.net/11104/0321867