RRC ID 61923
Author Makino T, Haruyama M, Katayama K, Terashima H, Tsunemi T, Miyazaki K, Terakawa M, Yamashiro K, Yoshioka R, Maeda H.
Title Phenotypic-screening generates active novel fetal globin-inducers that downregulate Bcl11a in a monkey model.
Journal Biochem Pharmacol
Abstract Heritable disorders associated with hemoglobin production are the most common monogenic disorders. These are mainly represented by disorders such as β-thalassemia and sickle cell disease. Induction of fetal hemoglobin (HbF) has been known to ameliorate the clinical severity of these β hemoglobinopathies. A high throughput phenotypic screening was used in this study to isolate novel compounds that may enhance the expression of γ-globin, the component of HbF, in human erythroid cell lines and primary erythroid progenitors derived from human CD34+ cells. The effect of lead compounds on epigenetic enzymes and key transcriptional factors was evaluated to identify their mode of action. One hit compound was further evaluated in vivo using monkey models. Among the ~18,000 compounds screened, 18 compounds were selected and tested to determine their ability to induce HbF in human erythroid cell lines and primary erythroid cells. One of these compounds, a 3-phenyl-isoxazole derivative, could potentially induce HbF in monkey bone marrow cells when administered orally. The compound downregulated negative transcriptional regulators of HbF, Bcl11a and LRF without inhibiting the known epigenetic enzymes. These studies demonstrated the advantages associated with phenotype-screening and identified novel fetal globin inducers that may be useful for treating hemoglobinopathies.
Volume 171
Pages 113717
Published 2020-1-1
DOI 10.1016/j.bcp.2019.113717
PII S0006-2952(19)30416-2
PMID 31751536
MeSH Animals Antigens, CD34 / metabolism Cell Differentiation / drug effects Cell Differentiation / genetics Cell Line Down-Regulation / drug effects Erythroblasts / cytology Erythroblasts / drug effects Erythroblasts / metabolism Fetal Hemoglobin / genetics* Fetal Hemoglobin / metabolism Gene Expression Regulation / drug effects* Hemoglobinopathies / genetics* Hemoglobinopathies / metabolism High-Throughput Screening Assays / methods Humans Macaca fascicularis Phenotype Repressor Proteins / genetics* Repressor Proteins / metabolism Xenobiotics / pharmacology* Zinc Fingers*
IF 4.96
Human and Animal Cells HUDEP-2(RCB4557)