Development of Mezigdomide-Based PROTACs Targeting HDAC1/2 for Fetal Hemoglobin Induction in Sickle Cell Disease

• Grant number: 25/15737-6
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: October 25, 2025
• End date: February 24, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Ana Lydssen da Silva Neves Nunes
• Supervisor: Antonello Mai
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Università degli Studi di Roma La Sapienza, Italy
• Associated to the scholarship: 23/13763-4 - Synthesis of new PROTAC compounds aiming to degradate HDAC-1 and -2 for Sickle Cell Disease, BP.IC

Abstract

Sickle cell disease (SCD) is a hereditary hematological disorder caused by a point mutation in the ¿-globin gene. In Brazil, it is estimated that approximately 3,500 children are born with SCD each year, and around 300,000 individuals carry the sickle cell trait. Although advances in potentially curative therapies-such as allogeneic hematopoietic stem cell transplantation and gene editing-offer promising prospects, their high cost and associated risks still limit accessibility and clinical applicability. Currently, four drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD: hydroxyurea, L-glutamine, crizanlizumab, and voxelotor. However, the latter two have been withdrawn from the market due to efficacy-related concerns. Among these, only hydroxyurea has consistently demonstrated the ability to increase fetal hemoglobin (HbF) levels, a well-established strategy for reducing morbidity and mortality in affected individuals. Nevertheless, due to adverse effects and suboptimal responses in certain patients, there is an urgent need for new therapeutic approaches with distinct mechanisms of action to induce HbF. The regulation of the ¿-globin gene, located on chromosome 11, involves repressive complexes and epigenetic enzymes such as histone deacetylases (HDACs). Selective inhibitors of HDAC1 and HDAC2 have proven effective in reactivating ¿-globin expression and increasing HbF levels, positioning these enzymes as promising therapeutic targets for SCD. In this context, PROTAC (Proteolysis Targeting Chimera) technology emerges as an innovative strategy for the selective degradation of proteins. By simultaneously recruiting the protein of interest and an E3 ubiquitin ligase, PROTACs promote ubiquitination and subsequent proteasomal degradation of the target protein. To date, the application of PROTACs in SCD remains largely unexplored, except for pioneering studies conducted by our research group, which developed the first degraders using pomalidomide as the cereblon (CRBN) E3 ligase ligand, yielding promising results in HbF induction.This project proposes the structural optimization of PROTAC ALY-14, previously synthesized by our group and already validated for its HbF-inducing potential. The current approach involves replacing the pomalidomide subunit with mezigdomide-a CRBN ligand with higher affinity and improved pharmacological properties-in order to deepen our understanding of structure-activity relationships, enhance HDAC1/2 degradation, and maximize fetal hemoglobin induction. This strategy represents an innovative and rationally designed approach toward the development of novel therapies for sickle cell disease. (AU)