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Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping.
Brehová, Petra; Reznícková, Eva; Skach, Krystof; Jorda, Radek; Dejmek, Milan; Vojácková, Veronika; Sála, Michal; Kovalová, Markéta; Dracínský, Martin; Dolníková, Alexandra; Strmen, Timotej; Kinnertová, Monika; Chalupský, Karel; Dvoráková, Alexandra; Gucký, Tomás; Mertlíková Kaiserová, Helena; Klener, Pavel; Nencka, Radim; Krystof, Vladimír.
Afiliação
  • Brehová P; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Reznícková E; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Skach K; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Jorda R; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Dejmek M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Vojácková V; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Sála M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Kovalová M; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Dracínský M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Dolníková A; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic.
  • Strmen T; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Kinnertová M; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Chalupský K; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Dvoráková A; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Gucký T; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Mertlíková Kaiserová H; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Klener P; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic.
  • Nencka R; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.
  • Krystof V; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
J Med Chem ; 66(16): 11133-11157, 2023 08 24.
Article em En | MEDLINE | ID: mdl-37535845
ABSTRACT
FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapse rates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocycles as central cores of FLT3 inhibitors, including thieno[3,2-d]pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[4,5-b]pyridine, pyrido[4,3-d]pyrimidine, and imidazo[1,2-b]pyridazine. Our assays revealed a series of imidazo[1,2-b]pyridazines with high potency against FLT3. Compound 34f showed nanomolar inhibitory activity against recombinant FLT3-ITD and FLT3-D835Y (IC50 values 4 and 1 nM, respectively) as well as in the FLT3-ITD-positive AML cell lines MV4-11, MOLM-13, and MOLM-13 expressing the FLT3-ITD-D835Y mutant (GI50 values of 7, 9, and 4 nM, respectively). In contrast, FLT3-independent cell lines were much less sensitive. In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with 34f at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridazinas / Leucemia Mieloide Aguda / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridazinas / Leucemia Mieloide Aguda / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Ano de publicação: 2023 Tipo de documento: Article