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

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

  • J Med Chem. 2021 Aug 12;64(15):10981-10996. doi: 10.1021/acs.jmedchem.1c00330.
Neetu Dayal 1,  Eva Řezníčková 2,  Delmis E Hernandez 1,  Miroslav Peřina 2,  Sandra Torregrosa-Allen 3,  Bennett D Elzey 3 4,  Jana Škerlová 5 6,  Haresh Ajani 5,  Stefan Djukic 5,  Veronika Vojáčková 2,  Martin Lepšík 5,  Pavlína Řezáčová 5 6,  Vladimír Kryštof 2,  Radek Jorda 2,  Herman O Sintim 1 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, Olomouc 78371, Czech Republic.
  • 3 Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4 Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907, United States.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nám. 2, Prague 16610, Czech Republic.
  • 6 Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, Prague 14220, Czech Republic.
  • 7 Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
PMID: 34288692 DOI: 10.1021/acs.jmedchem.1c00330
Abstract

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.

Figures
Products