title: Novel therapeutic candidates, identified by molecular modeling, induce γ-globin gene expression in vivo.
abstract: The β-hemoglobinopathies and thalassemias are serious genetic blood disorders affecting the β-globin chain of hemoglobin A (α(2)β(Α)(2)). Their clinical severity can be reduced by enhancing expression of fetal hemoglobin (γ-globin), producing HbF (α(2)γ(2,)). In studies reported here, γ-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 β-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 γ-globin inducing candidate therapeutics and validated the utility of in silico molecular modeling.
authors.affiliation: Cancer Center and Hemoglobinopathy-Thalassemia Research Unit, Boston University School of Medicine, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Boosalis
authors.forename: Serguei A
authors.initials: SA
authors.lastname: Castaneda
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
authors.forename: Rodwell
authors.initials: R
authors.lastname: Mabaera
authors.forename: Gary L
authors.initials: GL
authors.lastname: White
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lowrey
authors.forename: David W
authors.initials: DW
authors.lastname: Emery
authors.forename: Marthe-Sandrine Eiymo Mwa
authors.initials: MS
authors.lastname: Mpollo
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.forename: William A
authors.initials: WA
authors.lastname: Wargin
authors.forename: Regine
authors.initials: R
authors.lastname: Bohacek
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000284:Administration, Oral; D000740:Anemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001688:Biological Products / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002478:Cells, Cultured; D015195:Drug Design; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010215:Papio; D018962:Phlebotomy; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D055544:beta-Globins / Q000172:deficiency / Q000235:genetics; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001688:Biological Products; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin