Novel therapeutic candidates, identified by molecular modeling, induce gamma-globin gene expression in vivo.

摘要

The beta-hemoglobinopathies and thalassemias are serious genetic blood disorders affecting the beta-globin chain of hemoglobin A (alpha(2)beta(Alpha)(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 silico molecular modeling.