Scientific Publications

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

Publication TypeJournal Article
AuthorsBradner, JE, Mak R., Tanguturi SK, Mazitschek R., Haggarty SJ, Ross K., Chang CY, Bosco J., West N., Morse E., Lin K., Shen JP, Kwiatkowski NP, Gheldof N., Dekker J., DeAngelo DJ, Carr SA, Schreiber SL, Golub T. R., and Ebert BL
AbstractThe 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.
Year of Publication2010
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published (YYYY/MM/DD)2010/07/13
ISSN Number0027-8424