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Anemia
Volume 2012, Article ID 428137, 13 pages
http://dx.doi.org/10.1155/2012/428137
Research Article

FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

1Department of Pediatrics, Georgia Health Sciences University, Augusta, GA 30912, USA
2Department of Chemistry, University of Texas at Dallas, Richardson, TX 75083, USA
3Department of Pharmacological and Toxicological Chemistry, University of Naples Federico II, 80100 Naples, Italy
4Department of Molecular and Cell Biology, University of Texas at Dallas, TX 75080, USA
5Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Received 16 December 2011; Accepted 7 March 2012

Academic Editor: Solomon F. Ofori-Acquah

Copyright © 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.

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.