Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping

0574366 - ÚOCHB 2024 RIV US eng J - Journal Article
Břehová, Petra - Řezníčková, E. - Škach, Kryštof - Jorda, R. - Dejmek, Milan - Vojáčková, V. - Šála, Michal - Kovalová, M. - Dračínský, Martin - Dolníková, A. - Strmeň, Timotej - Kinnertová, M. - Chalupský, Karel - Dvořáková, Alexandra - Gucký, T. - Mertlíková-Kaiserová, Helena - Klener, P. - Nencka, Radim - Kryštof, V.
Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping.
Journal of Medicinal Chemistry. Roč. 66, č. 16 (2023), s. 11133-11157. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MZd(CZ) NU20-05-00472; GA MŠMT LX22NPO5102
Institutional support: RVO:61388963
Keywords : gene expression * highly potent
OECD category: Oncology
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.3c00575

FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapserates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocyclesas 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 withhigh 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 (GI(50) 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.
Permanent Link: https://hdl.handle.net/11104/0344703