Histone deacetylase inhibitors and hemoglobin F induction in β-thalassemia

Abstract

Epigenomic modifiers, such as histone deacetylase inhibitors, are compounds that regulate gene expression by interfering with the enzymatic machinery that maintains the proper chromatin structure of the nucleus. These compounds are at the forefront of novel therapeutic agents for the treatment of several diseases including cancer and genetic disorders such as β-thalassemia and sickle cell disease.Here we review the current understanding of the mechanism of action of epigenomic modifiers in the treatment of β-thalassemia and sickle cell anemia. We also discuss how the lessons learned from the study of the effects of these compounds on the β-globin locus, one of the best characterized regions of the human genome, might contribute to the understanding of the mechanism of action of these same compounds in cancer, where the specific regions of the genome that are responsible for the pathophysiology of the disease are often poorly defined.

Erythroblast enucleation

“…8 The histone acetylation status is regulated by two enzyme superfamilies, the histone acetyltransferases (HAT) and the histone deacetylases (HDAC) which catalyze, respectively, histone acetylation and deacetylation inducing open and closed chromatin configurations. 9 Eighteen distinct mammalian HDAC, grouped into four classes depending on their primary homology to the Saccharomyces cerevisiae deacetylases, have been reported. 9 HDAC function as multiprotein complexes with transcription factors, which ensure specificity by docking the complex to appropriate consensus sequences, and protein kinases, which modulate the activity by altering phosphorylation status.…”

“…9 Eighteen distinct mammalian HDAC, grouped into four classes depending on their primary homology to the Saccharomyces cerevisiae deacetylases, have been reported. 9 HDAC function as multiprotein complexes with transcription factors, which ensure specificity by docking the complex to appropriate consensus sequences, and protein kinases, which modulate the activity by altering phosphorylation status. Each HDAC is recruited into a specific complex, suggesting that each isoform may control specific cell functions.…”

“…9,12 The first clinical use of an HDAC inhibitor (suberoylanilide hydroxamic The effects of these two compounds on enucleation of human erythroblasts cultured in the presence of erythropoietin are presented on the left. A compound inhibits HDAC activity by irreversibly binding to the catalytic domain of the enzyme.…”

“…The pharmacophore model for HDACi, such as SAHA or trichostatin A, which mimic the structure of the substrate includes four domains: a zinc binding group (ZBG), a hydrophobic spacer (HS), a connection unit (CU) and an interaction domain with the rim of the catalytic pocket of the enzyme (CAP). 9,12 By altering the chemical residues of these domains, pharmaceutical chemists are synthesizing new generation HDACi, such as the compound aroyl-pyrrolyl hydroxyl-amide 9 (APHA 9) and uracyl-based hydroxyl-amide 24 (UBHA 24) described in this Figure. The inhibitory activity (ID50) of SAHA, APHA 9 and UBHA 24 against purified human HDAC4 and HDAC1, used as examples of class II and class I HDAC, is reported, for comparison. APHA 9 and UBHA 24 were identified by screening a library of 24 new HDACi for their ability to reactivate g-globin expression in erythroblasts generated ex-vivo from normal donors and from β°-thalassemic patients.…”

“…12 The recognition of isoform-specific HDAC functions has provided a paradigm-shift for the design of HDAC inhibitors. The aim of current studies is to increase clinical efficacy by identifying the HDAC isoform to be targeted and then designing HDAC inhibitors specific for that isoform 9,12 This search has been facilitated by the availability of crystallographic data on the binding of the catalytic domain of bacterial HDAC with trichostatin A which led to the development of a pharmacophore model for HDAC inhibitors 9 ( Figure 3). Based on this model, new generation HDAC inhibitors have been synthesized and are currently in clinical trials.…”