Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

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Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

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Title: Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease
Author: Bradner, James Elliott; Mak, Raymond Heungwing; Tanguturi, Shyam Kumar; Mazitschek, Ralph; Haggarty, Stephen John; Ross, Kenneth N; Chang, Cindy Y.; Bosco, Jocelyn; West, Nathan; Morse, Elizabeth; Lin, Katherine; Shen, John Paul; Kwiatkowski, Nicholas Paul; Gheldof, Nele; Dekker, Job; DeAngelo, Daniel J.; Carr, Steven A.; Schreiber, Stuart L.; Golub, Todd Robert; Ebert, Benjamin L.

Note: Order does not necessarily reflect citation order of authors.

Citation: Bradner, James E., Raymond Mak, Shyam K. Tanguturi, Ralph Mazitschek, Stephen J. Haggarty, Kenneth Ross, Cindy Y. Chang, et al. 2010. “Chemical Genetic Strategy Identifies Histone Deacetylase 1 (HDAC1) and HDAC2 as Therapeutic Targets in Sickle Cell Disease.” Proceedings of the National Academy of Sciences 107 (28) (June 28): 12617–12622. doi:10.1073/pnas.1006774107.
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Abstract: The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.
Published Version: doi:10.1073/pnas.1006774107
Other Sources: https://www.ncbi.nlm.nih.gov/pubmed/20616024
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29400932
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