Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS

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.

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Publication Details

Journal
Leukemia & lymphoma/Leukemia and lymphoma
Published
2024-12-27
DOI
https://doi.org/10.1080/10428194.2024.2444479
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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article

Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS

Kith Pradhan, Rahul Sanawar, Emma Rabinovich, Michael Lahn et al.
Leukemia & lymphoma/Leukemia and lymphoma
Acute Myeloid Leukemia Research
article

Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS

Kith Pradhan, Rahul Sanawar, Emma Rabinovich, Michael Lahn, Jinghang Zhang, Marcel A. Deken, Srinivas Alluri, Jonathan M. Yingling, Aditi Shastri, Sarah Aminov, Leya Schwartz, Bianca Rivera-Peña, Nandini Ramachandra, Shanisha Gordon-Mitchell, Scott Sawyer, Charan Thej Reddy Vegivinti, Ariel Fromowitz, Fnu Aodengtuya, Opeyemi Ajibade, Amit K. Verma, Srabani Sahu, Rongbao Zhao, Victor Thiruvananthapuram
article en

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.

Leukemia & lymphoma/Leukemia and lymphomaVol. 66(5)
Albert Einstein College of Medicine (US), Montefiore Medical Center (US), Vectura (United Kingdom) (GB), Cloud Pharmaceuticals (United States) (US), Profectus Biosciences (United States) (US), Ashland (United States) (US)
Zero hunger
Openalex Percentile: Top 56%
Acute Myeloid Leukemia Research
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