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Strategies for intervention in gamma-globin gene repressor complexes containing Histone Deacetylase (HDAC-1 and HDAC-2) using small molecules

Grant number: 23/05739-6
Support Opportunities:Regular Research Grants
Duration: November 01, 2023 - October 31, 2025
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Jean Leandro dos Santos
Grantee:Jean Leandro dos Santos
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated researchers: Carolina Lanaro ; Cauê Benito Scarim ; Chung Man Chin ; Dulcinéia Martins de Albuquerque ; Fernando Ferreira Costa ; Fernando Rogério Pavan ; James Hodgkinson

Abstract

Sickle cell anemia (SCA) is one of the most prevalent genetic hematological diseases worldwide. Although procedures such as allogeneic hematopoietic stem cell transplantation or gene editing are curative approaches, limitations related to the cost and risk of these procedures are still barriers to be overcome. In addition, given the different phenotypes of SCA, 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 has been shown to be effective in reducing morbidity and mortality. Gene regulation of gamma-globin on chromosome 11 is carried out by repressor complexes and enzymes involved in epigenetic mechanisms, such as histone deacetylase (HDAC). Recently, the company Acetylon Pharmaceuticals described the promising in vivo results of the HDAC -1/-2 inhibitor (ACY-957). Although encouraging, it is known that HDAC -1/-2 do not act alone, but forming the catalytic subunit of multiple transcriptional regulatory complexes (i.e. NurD and CoREST). A more effective therapeutic strategy for HbF induction may therefore be the development of inhibitors that target a given complex. This is important as 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 use of two strategies directed to the complexes that: a) induce the degradation of HDAC -1/-2 using the PROTACs approach and; b) design 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 in 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. (AU)

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