Planning, synthesis and pharmacological evaluation of dual inhibitors of histone deacetylase and lysine demethylase (LSD-1) as inducers of fetal hemoglobin production

Abstract

Despite scientific advances, procedures involving the allogeneic hematopoietic stem cell transplantation or gene editing that have emerged as a curative strategy in the last years, sickle cell disease (SCD) still remains one of the most prevalent genetic hematological diseases in the world. Difficulties related to curative approaches, such as cost and risk of procedures, are still barriers to be overcome. Furthermore, given the different phenotypes of AF, drug treatment will still be necessary for some patients who do not meet the criteria established in curative approaches. Among the various strategies for searching for new drugs, the induction of fetal hemoglobin (HbF) is valid and effective in reducing patient morbidity and mortality. Gene regulation of gamma-globin expression on chromosome 11 is carried out by repressive complexes and enzymes involved in epigenetic mechanisms, involving enzymes such as histone deacetylase (HDAC) and lysine demethylase-1. The gene regulation occurs through the formation of catalytic subunits of multiple transcriptional regulatory complexes (e.g. NurD and CoREST). A more effective therapeutic strategy for HbF induction may, therefore, be the development of inhibitors that target a specific complex, rather than the isolated inhibition of enzymes. This is important because these complexes have distinct biological functions and therefore it makes sense to target a particular complex rather than, for example, simultaneously targeting all complexes containing HDAC -1/-2. In this project, we propose the design, synthesis and evaluation of conjugates that inhibit both LSD-1 / HDAC -1/ -2 enzymes present in the CoREST complex. It is expected to evaluate the effect of these new approaches on the induction of gamma-globin and HbF gene expression, in order to identify a new therapeutic alternative to hydroxyurea in the treatment of sickle cell anemia.