Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.

1st Department of Internal Medicine Hematology General University Hospital and 1st Faculty of Medicine Charles University 12808 Prague Czech Republic

1st Faculty of Medicine Institute of Pathological Physiology Charles University 12108 Prague Czech Republic

Department of Experimental Biology Faculty of Science Palacký University Olomouc Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 1192 12 77900 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 5 77900 Olomouc Czech Republic

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