4.7 Article

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Journal

Publisher

MDPI
DOI: 10.3390/ijms232416169

Keywords

FLT3; cyclin-dependent kinase; purine; inhibitor; acute myeloid leukemia

Funding

  1. European Union-Next Generation EU
  2. Czech Science Foundation [LX22NPO5102]
  3. Ministry of Health of the Czech Republic [20-25308S, 21-06553S]
  4. Palacky University Olomouc [NV19-08-00144]
  5. [IGA_PrF_2022_007]
  6. [IGA_PrF_2022_022]

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The therapy of FLT3-positive acute myeloid leukemia remains complicated, despite the availability of newly approved kinase inhibitors. This study reports the development of a new FLT3 inhibitor and provides structure-activity relationship studies. Cellular analyses and in vivo experiments demonstrate the inhibitory activity of the compound.
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.

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