Novel antileukemic compound with sub-micromolar potency against STAT5 addicted myeloid leukemia cells

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.

Chemoresistance; Medicinal chemistry; Myeloid leukemias; Pharmacological inhibitors; STAT5; Suzuki coupling.