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A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies
Peterson, Kenneth R. Costa, Flávia C. Fedosyuk, Halyna Neades, Renee Y. Chazelle, Allen M. Zelenchuk, Lesya Fonteles, Andrea H. Dalal, Parmita Roy, Anuradha Chaguturu, Rathnam
Peterson, Kenneth R.
Costa, Flávia C.
Fedosyuk, Halyna
Neades, Renee Y.
Chazelle, Allen M.
Zelenchuk, Lesya
Fonteles, Andrea H.
Dalal, Parmita
Roy, Anuradha
Chaguturu, Rathnam
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Abstract
Decades of research have established that the most effective treatment for sickle cell disease (SCD) is increased fetal
hemoglobin (HbF). Identification of a drug specific for inducing c-globin expression in pediatric and adult patients, with
minimal off-target effects, continues to be an elusive goal. One hurdle has been an assay amenable to a high-throughput
screen (HTS) of chemicals that displays a robust c-globin off-on switch to identify potential lead compounds. Assay systems developed in our labs to understand the mechanisms underlying the c- to b-globin gene expression switch during
development has allowed us to generate a cell-based assay that was adapted for a HTS of 121,035 compounds. Using
chemical inducer of dimerization (CID)-dependent bone marrow cells (BMCs) derived from human c-globin promoter-firefly
luciferase b-globin promoter-Renilla luciferase b-globin yeast artificial chromosome (c-luc b-luc b-YAC) transgenic mice, we were able to identify 232 lead chemical compounds that induced c-globin 2-fold or higher, with minimal or no b-globin
induction, minimal cytotoxicity and that did not directly influence the luciferase enzyme. Secondary assays in CIDdependentwild-type b-YAC BMCs and human primary erythroid progenitor cells confirmed the induction profiles of sevenof the 232 hits that were cherry-picked for further analysis.
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This is the published version, also available here, http//dx.doi.org/10.1371/journal.pone.0107006.
Date
2014-09-16
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Public Library of Science
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Peterson KR, Costa FC, Fedosyuk H, Neades RY, Chazelle AM, et al. (2014) "A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies." PLoS ONE 9(9): e107006. http://dx.doi.org/10.1371/journal.pone.0107006