A switch from fetal-globin gene (γ-globin, HBG1/2) to adult β-globin gene (HBB) transcription occurs during erythropoiesis (“maturational switch”) and requires the repression of HBG1/2 by druggable repressing epigenetic enzymes (CoRs). Gene therapy targets the DNA-binding factors that recruit the CoR enzymes. An alternative approach is to inhibit the enzyme elements in the hub (eg, LSD1, HDACs, DNMT1) with small molecules. Limitations of available clinical-stage CoR enzyme inhibitors are shown, including lessons learned for moving forward. Small molecule inhibitors for other CoR enzymes in the hub, CHD4 and CBX5, are in a preclinical stage of development.

A switch from fetal-globin gene (γ-globin, HBG1/2) to adult β-globin gene (HBB) transcription occurs during erythropoiesis (“maturational switch”) and requires the repression of HBG1/2 by druggable repressing epigenetic enzymes (CoRs). Gene therapy targets the DNA-binding factors that recruit the CoR enzymes. An alternative approach is to inhibit the enzyme elements in the hub (eg, LSD1, HDACs, DNMT1) with small molecules. Limitations of available clinical-stage CoR enzyme inhibitors are shown, including lessons learned for moving forward. Small molecule inhibitors for other CoR enzymes in the hub, CHD4 and CBX5, are in a preclinical stage of development.

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