Design, synthesis and evaluation of dual inhibitors of histone deacetylase and lysine-specific demethylase 1 as inducers of fetal hemoglobin production

• Grant number: 25/08471-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: January 31, 2029
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Mateus Mello de Souza
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Despite significant scientific advances, including curative approaches such as allogeneic hematopoietic stem cell transplantation and CRISPR-based gene editing, sickle cell disease (SCD) remains one of the most prevalent genetic hematological disorders worldwide. Obstacles such as high costs, procedural risks, and limited accessibility still hinder the widespread adoption of these therapies. Additionally, given the distinct phenotypes of SCD, pharmacological treatment will still be necessary for some patients who do not meet the established criteria for curative approaches. Among therapeutic strategies, the induction of fetal hemoglobin (HbF)-a clinically validated approach-has proven effective in reducing morbidity and mortality by mitigating the pathological consequences of sickle hemoglobin. The expression of gamma-globin, encoded on chromosome 11, is tightly regulated by repressive epigenetic complexes. Among these, the NuRD and CoREST complexes play a significant role by recruiting enzymes such as histone deacetylases (HDAC-1/2) and lysine-specific histone demethylase 1A (LSD1/KDM1A) to suppress gamma-globin transcription. Current therapeutic strategies primarily target individual enzymes, such as HDAC-1/2 or LSD1. However, these enzymes function within multiprotein complexes with distinct biological roles, suggesting that the selective inhibition of a specific complex could enhance selectivity, safety, and therapeutic efficacy. This project aims to design, synthesize, and evaluate the pharmacological potential of novel dual inhibitors targeting the CoREST complex. (AU)