New Inhibitor Targeting Signal Transducer and Activator of Transcription 5 (STAT5) Signaling in Myeloid Leukemias

Ludovic Juen (1) , Marie Brachet-Botineau (1) , Cecile Parmenon (1) , Jerome Bourgeais (1) , Olivier Herault (2) , Fabrice Gouilleux (1) , Marie-Claude Viaud-Massuard (1) , Gildas Prié (1)

1 GICC UMR 7292 CNRS - Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017]
2 CNRS GDR 3697 MicroNiT

Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.

Domains: Chemical Sciences; Chemical Sciences; Medicinal Chemistry

Ludovic Juen, Marie Brachet-Botineau, Cecile Parmenon, Jerome Bourgeais, Olivier Herault, et al.. New Inhibitor Targeting Signal Transducer and Activator of Transcription 5 (STAT5) Signaling in Myeloid Leukemias. Journal of Medicinal Chemistry, 2017, 60 (14), pp.6119-6136. ⟨10.1021/acs.jmedchem.7b00369⟩. ⟨hal-02411721⟩