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
{"title":"转化生长因子受体I型（TGF-βRI）激酶抑制剂IOA-359和IOA-360可刺激MDS患者的红细胞生成。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18047,"journal":{"name":"Leukemia & Lymphoma","volume":" ","pages":"1-10"},"PeriodicalIF":2.2000,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transforming growth factor beta receptor type I (TGF-βRI) kinase inhibitors IOA-359 and IOA-360 stimulate erythropoiesis in MDS.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":18047,\"journal\":{\"name\":\"Leukemia & Lymphoma\",\"volume\":\" \",\"pages\":\"1-10\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2024-12-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia & Lymphoma\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/10428194.2024.2444479\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia & Lymphoma","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/10428194.2024.2444479","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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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Leukemia & Lymphoma in its fourth decade continues to provide an international forum for publication of high quality clinical, translational, and basic science research, and original observations relating to all aspects of hematological malignancies. The scope ranges from clinical and clinico-pathological investigations to fundamental research in disease biology, mechanisms of action of novel agents, development of combination chemotherapy, pharmacology and pharmacogenomics as well as ethics and epidemiology. Submissions of unique clinical observations or confirmatory studies are considered and published as Letters to the Editor
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