Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors
Monika Tomanová1, Karolína Kozlanská2, Radek Jorda2
1Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 1192/12, 77900 Olomouc, Czech Republic.
Abstract:
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.
Insights
Researchers developed novel dual-targeting purine compounds to treat FLT3-positive acute myeloid leukemia (AML). Compound 15a shows high selectivity for FLT3 kinase, inhibiting cancer cell growth in preclinical models.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) with FLT3 mutations presents therapeutic challenges.
- Existing FLT3 kinase inhibitors face efficacy limitations.
- Dual-targeting strategies offer a promising approach to overcome resistance.
Purpose of the Study:
- To design and synthesize novel 8-oxopurine derivatives as FLT3 inhibitors.
- To investigate the structure-activity relationships (SAR) of these compounds.
- To identify potent and selective dual inhibitors for FLT3-positive AML.
Main Methods:
- Synthesis of 2,7,9-trisubstituted 8-oxopurines.
- Structure-activity relationship studies to optimize kinase inhibition.
- In vitro cellular assays (MV4-11 cells) assessing FLT3 autophosphorylation and downstream signaling (STAT5, ERK1/2).
- In vivo evaluation in a mouse xenograft model.
Main Results:
- Substituents at positions 7 and 9 modulated activity against CDK4 and FLT3 kinases.
- An isopropyl group at position 7 enhanced selectivity for FLT3 kinase.
- Compound 15a demonstrated potent inhibition of FLT3 autophosphorylation and downstream signaling in nanomolar concentrations.
- Compound 15a exhibited anti-leukemic activity in a preclinical mouse model.
Conclusions:
- Novel 8-oxopurine derivatives effectively inhibit FLT3 kinase.
- Compound 15a represents a promising candidate for treating FLT3-positive AML.
- Dual-targeting strategies involving FLT3 inhibition warrant further investigation.
