FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

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FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

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Title: FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors
Author(s):
Makala, L.;
Di Maro, Salvatore;
Lou, Tzu-Fang;
Sivanand, S.;
Ahn, Jung-Mo;
Pace, B. S.
Format: Text
Item Type: Article
Keywords: Romidepsin
Fetal Hemoglobin
Anemia, Sickle Cell
Abstract: Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD. © 2012 Levi Makala et al.
ISSN: 2090-1267
Persistent Link: http://dx.doi.org/10.1155/2012/428137
http://hdl.handle.net/10735.1/3067
Terms of Use: © 2012 Levi Makala et al. "This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited."

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