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

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

doi:10.1080/10428194.2024.2444479

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

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

Scott Sawyer, Michael Lahn, Amit Verma

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Pages (from-to)	920-929
Number of pages	10
Journal	Leukemia and Lymphoma
Volume	66
Issue number	5
DOIs	https://doi.org/10.1080/10428194.2024.2444479
State	Published - 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ALK5 inhibitors
Acute Myeloid Leukemia (AML)
IOA-359 and IOA-360
Myelodysplastic Syndrome (MDS)
TGF-β inhibitors

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

Access to Document

10.1080/10428194.2024.2444479

Cite this

Ramachandra, N., Vegivinti, C. T. R., 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., ... Verma, A. (2025). Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS. Leukemia and Lymphoma, 66(5), 920-929. https://doi.org/10.1080/10428194.2024.2444479

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 & Verma, A 2025, 'Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS', Leukemia and Lymphoma, vol. 66, no. 5, pp. 920-929. https://doi.org/10.1080/10428194.2024.2444479

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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.",

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AU - Ajibade, Opeyemi

AU - Gordon-Mitchell, Shanisha

AU - Shastri, Aditi

AU - Deken, Marcel

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AU - Sawyer, Scott

AU - Lahn, Michael

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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