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Updated: Jun 4, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Novel antileukemic compound with sub-micromolar potency against STAT5 addicted myeloid leukemia cells
Marion Polomski1, Marie Brachet-Botineau2, Benjamin Victoir1
1INSERM UMR 1100 CEPR, Research Center for Respiratory Diseases, Team 2 "Proteolytic Enzymes and Their Pharmacological Targeting in Lung Diseases", 10 Boulevard Tonnellé, 37032, Tours, France.
Abstract:
Signal Transdcer and Activator of Transcription 5A and 5B (STAT5A/5B) are key effectors of tyrosine kinase oncogenes in myeloid leukemias. It is now clearly evidenced that inhibition of STAT5A/5B not only blocks the growth and survival of myeloid leukemia cells but also overcomes the resistance of leukemic cells to chemotherapy. Previous screening experiments allowed us to identify 17f as a lead compound with promising antileukemic activity that blocks the phosphorylation and transcriptional activity of STAT5A/5B in myeloid leukemia cells addicted to these proteins. In light of these findings, we initiated further pharmacomodulations of 17f to develop new derivatives with enhanced antileukemic activity. Our screening assays identified 14a, an aminopyrimidine derivative of 17f, as a new lead compound that: 1) blocks the growth and survival of myeloid leukemia cells at sub-micromolar concentrations, 2) targets the phosphorylation of STAT5 but also the expression of STAT5B and 3) relieves the resistance of Chronic and Acute Myeloid leukemia cells to conventional chemotherapy.
Insights
A novel compound, 14a, effectively inhibits myeloid leukemia cell growth by targeting Signal Transducer and Activator of Transcription 5A/5B (STAT5A/5B). This new derivative also overcomes chemotherapy resistance in both Chronic and Acute Myeloid leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Signal Transducer and Activator of Transcription 5A and 5B (STAT5A/5B) are crucial in myeloid leukemias.
- Inhibiting STAT5A/5B blocks leukemia cell growth and survival, and overcomes chemotherapy resistance.
Purpose of the Study:
- To develop novel derivatives of the lead compound 17f with enhanced antileukemic activity.
- To identify new compounds targeting STAT5A/5B signaling in myeloid leukemias.
Main Methods:
- Pharmacological modification of a lead compound (17f).
- Screening assays to evaluate antileukemic activity and mechanism of action.
- Assessment of STAT5 phosphorylation and expression levels.
Main Results:
- Identified 14a, an aminopyrimidine derivative, as a potent antileukemic compound.
- 14a inhibits myeloid leukemia cell growth at sub-micromolar concentrations.
- 14a targets STAT5 phosphorylation and STAT5B expression, overcoming chemotherapy resistance.
Conclusions:
- Compound 14a demonstrates significant potential as a therapeutic agent for myeloid leukemias.
- 14a offers a dual mechanism of action by inhibiting STAT5 signaling and overcoming drug resistance.
- Further development of 14a could lead to improved treatments for Chronic and Acute Myeloid leukemia.
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