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

FLT3 kinase is a potential drug target in acute myeloidleukemia(AML). Patients with FLT3 mutations typically have higher relapserates and worse outcomes than patients without FLT3 mutations. Inthis 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 assaysrevealed a series of imidazo[1,2-b]pyridazines withhigh potency against FLT3. Compound 34f showed nanomolarinhibitory activity against recombinant FLT3-ITD and FLT3-D835Y (IC50 values 4 and 1 nM, respectively) as well as in the FLT3-ITD-positiveAML cell lines MV4-11, MOLM-13, and MOLM-13 expressing the FLT3-ITD-D835Ymutant (GI(50) values of 7, 9, and 4 nM, respectively). Incontrast, FLT3-independent cell lines were much less sensitive. Invitro experiments confirmed suppression of FLT3 downstream signalingpathways. Finally, the treatment of MV4-11 xenograft-bearing micewith 34f at doses of 5 and 10 mg/kg markedly blockedtumor growth without any adverse effects.