期刊
BLOOD CELLS MOLECULES AND DISEASES
卷 47, 期 2, 页码 107-116出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bcmd.2011.04.008
关键词
Butyrate; Fetal hemoglobin; Hemoglobinopathy; Small molecules
类别
资金
- National Institutes of Health [DK-52962, HL-78276, HL-52243, HL-73442, CA-101992, HL-007501-28]
- Department of Defense [DAMD 17-03-1-0213]
- Canadian Institutes of Health Research/Canadian Blood Services [210399]
The beta-hemoglobinopathies and thalassemias are serious genetic blood disorders affecting the beta-globin chain of hemoglobin A (alpha(2)beta(A)(2)). Their clinical severity can be reduced by enhancing expression of fetal hemoglobin (gamma-globin), producing HbF (alpha(2)gamma(2)). In studies reported here, gamma-globin induction by 23 novel, structurally-unrelated compounds, which had been predicted through molecular modeling and in silico screening of a 13,000 chemical library, was evaluated in vitro in erythroid progenitors cultured from normal subjects and beta-thalassemia patients, and in vivo in transgenic mice or anemic baboons. Four predicted candidates were found to have high potency, with 4- to 8-fold induction of HbF. Two of these compounds have pharmacokinetic profiles favorable for clinical application. These studies thus effectively identified high potency gamma-globin inducing candidate therapeutics and validated the utility of in silica molecular modeling. (C) 2011 Elsevier Inc. All rights reserved.
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