1. Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS.
- Author
-
Ramachandra N, Vegivinti CTR, Sahu S, Sanawar R, Rivera-Peña B, Aminov S, Fromowitz A, Zhang J, Aodengtuya F, Pradhan K, Zhao R, Schwartz L, Alluri S, Thiruvananthapuram V, Rabinovich E, Ajibade O, Gordon-Mitchell S, Shastri A, Deken M, Yingling JM, Sawyer S, Lahn M, and Verma A
- Abstract
Overactivation of the Transforming Growth Factor Beta (TGF-β) pathway is implicated in the pathogenesis of cytopenias in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML). IOA-359 and IOA-360 are potent small molecule inhibitors of the TGF-beta Receptor type I kinase (TGF-βRI, also referred to as ALK5, activin receptor-like kinase 5) that abrogate SMAD phosphorylation in hematopoietic cell lines. Both inhibitors were able to inhibit TGF-β mediated gene transcription at specific doses. ALK5 inhibitors abrogated the growth inhibitory effects of TGF-β on healthy hematopoietic stem cells and stimulated hematopoietic differentiation in cell lines and MDS/AML specimens. These data demonstrate preclinical efficacy of two novel ALK5 inhibitors, IOA-359 and IOA-360, in stimulating erythroid differentiation in MDS and AML.
- Published
- 2024
- Full Text
- View/download PDF