The state of the art of fetal hemoglobin-inducing agents

Sickle cell anemia (SCA) is a hematological genetic disorder caused by a mutation in the gene of the β-globin. Pharmacological treatments will continue to be an important approach, including the strategy to induce fetal hemoglobin (HbF). Here, we analyzed the articles described in the literature regarding the drug discovery of HbF inducers. The main approaches for such strategy will be discussed, highlighting those most promising. The comprehension of the mechanisms involved in the β-globin regulation is the main key to design new drugs to induce HbF. Among the strategies, gamma-globin regulation by epigenetic enzymes seems to be a promising approach to be pursued, although the comprehension of the selectivity role for those new drugs is crucial to reduce adverse effects. The low druggability of transcription factors and their vital role in embryonic human development are critical points that should be taken in account for drug design. The guanylate cyclase and the NO/cGMP signaling pathway seem to be promising not only for HbF induction, but also for the protective effects in the cardiovascular system. The association of drugs acting through different mechanisms to induce HbF seems to be promising for the discovery of new drugs.