Small molecule therapeutics to treat the β-globinopathies

Abstract

Purpose of review: The current review focuses on recent insights into the development of small molecule therapeutics to treat the β-globinopathies.

Recent findings: Recent studies of fetal γ-globin gene regulation reveal multiple insights into how γ-globin gene reactivation may lead to novel treatment for β-globinopathies.

Summary: We summarize current information regarding the binding of transcription factors that appear to be impeded or augmented by different hereditary persistence of fetal hemoglobin (HPFH) mutations. As transcription factors have historically proven to be difficult to target for therapeutic purposes, we next address the contributions of protein complexes associated with these HPFH mutation-affected transcription factors with the aim of defining proteins that might provide additional targets for chemical molecules to inactivate the corepressors. Among the enzymes associated with the transcription factor complexes, a group of corepressors with currently available inhibitors were initially thought to be good candidates for potential therapeutic purposes. We discuss possibilities for pharmacological inhibition of these corepressor enzymes that might significantly reactivate fetal γ-globin gene expression. Finally, we summarize the current clinical trial data regarding the inhibition of select corepressor proteins for the treatment of sickle cell disease and β-thalassemia.

Figure1.. Primary and secondary targets of small molecule inhibitors for treating pathological symptoms of SCD.

A. Compounds [indicated by the red and white “pill”] targeting the proximal causes of SCD act to reduce sickling in RBCs either by directly reducing deoxygenated HbS polymerization [left; orange a-globin plus blue b^S- HbS tetrameric polymers] or indirectly by inducing HbF [right, orange α-globin + yellow γ-globin chains], which interrupt and terminate sickle HbS polymerization. B. Both acute and chronic complications result from increased ssRBC adherence to endothelial cells [brown] and leukocytes [grey with irregular nuclei] resulting in multicellular aggregates. These, in turn, cause cellular and molecular pathologies leading to downstream sequelae [multiorgan damage, brain infarcts, acute chest and bone pain and shortened lifespan]. These molecular pathologies are the target of therapies intended to reduce vascular occlusion and chronic injury.

Figure 2.. HPFH mutations and the TFs known or hypothesized to be affected.

A. The position of the HPFH mutations and the nucleotide changes is indicated below the identical γ-globin promoter sequences. The approximate positions and identities of the best-characterized transcription factors are shown above the sequence, while mutations that lead to ectopic binding of activating transcription factors are highlighted in dark blue lettering. B. Epigenetic enzymes associated with fetal globin proximal promoter binding TFs and the epigenetic modification of each enzyme. G [GATA1]; Z [ZBTB7A]; T [TR2/TR4]; B [Bcl11a]; L [LYAR]. M [methylation of DNA or histone, + or − indicates the activity of that enzyme on that site]; A [histone acetylation]; U [histone ubiquitination].