Synthesis and pharmacological evaluation of PROTAC-HDAC inhibitors-based compounds for sickle cell disease

Abstract

Sickle Cell Disease (SCD) is the most prevalent hematological genetic disease worldwide. In Brazil, it afflicts, annually, about 3,500 newborns and approximately 300,000 cases of sickle trait carriers have been reported. Vaso-occlusive crises, intense pain and organ infarcts are among the main symptoms and complications of SCD, leading to high rates of morbidity and mortality. Currently, there are only four drugs approved by FDA for SCD treatment: hydroxyurea (HU), L-glutamine, voxelotor and the monoclonal antibody crizanlizumab, being the last three drugs approved from 2017. SCD patients in which the phenotype is characterized by high production of fetal hemoglobin (HbF) exhibits diminished severity of the symptoms. Thus, HbF induction is a validated approach and the regulation of enzymes involved in the epigenetic controls seems to be a promising opportunity to find out new small molecules able to increase gamma-globin expression and HbF production. Although HU increases the HbF levels, long-term treatment drawbacks such as genotoxicity and myelosuppression demands the search for new safe and effective drugs. Histone deacetylases (HDAC) 1 and 2 are epigenetic enzymes involved the gamma-globin gene silencing during the globin switching, which occurs after birth. HDAC 1 and 2 inhibition promote an increase in the gamma-globin expression and HbF production, being a potential target for SCD. Proteolysis targeting chimera (PROTACs) is an approach used for degrading specific enzymes by anchoring the target protein on one side and an E3 ligase enzyme on the other side of the PROTAC molecule, resulting in the target enzyme ubiquitination and, later, degradation by the proteasome complex. For SCD the use of PROTAC approach was not investigated yet. Therefore, the present project aims to synthesize and evaluate the feasibility of the PROTAC approach for HDAC 1 and 2 degradation as a new strategy to induce gamma-globin expression and HbF production representing a new useful approach for SCD treatment. (AU)