TY - JOUR
T1 - Novel histone deacetylase inhibitor CT-101 induces γ-globin gene expression in sickle erythroid progenitors with targeted epigenetic effects
AU - Junker, Louis H.
AU - Li, Biaoru
AU - Zhu, Xingguo
AU - Koti, Sivanagireddy
AU - Cerbone, Ryan E.
AU - Hendrick, Clifford L.
AU - Sangerman, Jose
AU - Perrine, Susan
AU - Pace, Betty S.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/3
Y1 - 2022/3
N2 - Induction of fetal hemoglobin (HbF) expression ameliorates the clinical severity and prolong survival in persons with sickle cell disease (SCD). Hydroxyurea (HU) is the only FDA-approved HbF inducer however, additional therapeutics that produce an additive effect in SCD are needed. To this end, development of potent Class I histone deacetylase inhibitors (HDACi) for HbF induction represents a rational molecularly targeted approach. In studies here, we evaluated CT-101, a novel Class I-restricted HDACi, a Largazole derivative, for pharmacodynamics, cytotoxicity, and targeted epigenetic effects. In SCD-derived erythroid progenitors, CT-101 induced HbF expression with additive activity in combination with HU. CT-101 preferentially activated γ-globin gene transcription, increased acetylated histone H3 levels, and conferred an open chromatin conformation in the γ-globin promoter. These data indicate CT-101 represents a strong potential candidate as a molecularly targeted inducer of HbF.
AB - Induction of fetal hemoglobin (HbF) expression ameliorates the clinical severity and prolong survival in persons with sickle cell disease (SCD). Hydroxyurea (HU) is the only FDA-approved HbF inducer however, additional therapeutics that produce an additive effect in SCD are needed. To this end, development of potent Class I histone deacetylase inhibitors (HDACi) for HbF induction represents a rational molecularly targeted approach. In studies here, we evaluated CT-101, a novel Class I-restricted HDACi, a Largazole derivative, for pharmacodynamics, cytotoxicity, and targeted epigenetic effects. In SCD-derived erythroid progenitors, CT-101 induced HbF expression with additive activity in combination with HU. CT-101 preferentially activated γ-globin gene transcription, increased acetylated histone H3 levels, and conferred an open chromatin conformation in the γ-globin promoter. These data indicate CT-101 represents a strong potential candidate as a molecularly targeted inducer of HbF.
KW - Epigenetics
KW - Fetal hemoglobin
KW - Histone deacetylase inhibitor
KW - Sickle cell disease
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U2 - 10.1016/j.bcmd.2021.102626
DO - 10.1016/j.bcmd.2021.102626
M3 - Article
C2 - 34856533
AN - SCOPUS:85120048339
SN - 1079-9796
VL - 93
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
M1 - 102626
ER -