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Design and synthesis of new inhibitors and degraders (PROteolysis TArgeting Chimera - PROTAC) of histone deacetylases (HDACs) 1 and 2 for sickle cell anemia

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Aline Renata Pavan
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 2023-07-13.
Institution: Universidade Estadual Paulista (Unesp). Instituto de Química. Araraquara
Defense date:
Advisor: Jean Leandro dos Santos

Sickle cell anemia (SCA) is a hereditary hemoglobinopathies caused by a single mutation in the gene of β-globin. Due to this mutation, a mutated hemoglobin is formed (HbS) leading to polymerization and causing irreversible changes in the morphology of red blood cells, which get a sickle shape e is responsible for the pathophysiology of the disease. Among the strategies described in the literature for the treatment of SCA is the induction of the expression of γ-globin and production of fetal hemoglobin (HbF), which is able to diminish the symptoms by reducing the polymerization and was the chosen strategy in this work. Epigenetic enzymes called histone deacetylases (HDACs) 1 and 2 were explored as targets for the development of new γ-globin and HbF inducers. Therefore, this work was divided into two parts: 1) Design, synthesis and pharmacological evaluation of new HDAC 1 and 2 inhibitors; 2) Design, synthesis and pharmacological evaluation of new PROTACs for degradation of HDAC 1 and 2. In the part 1, it was synthesized 24 intermediates and 7 final products in yields ranging from 29 and 85%. Two of the most promisor compounds presented IC50 values ranging from 17 to 950 nM and interesting selectivity towards HDACs 1 and 2. Preliminary assay in erythroleukemic cells (K562) demonstrated that both compounds were able to increase γ-globin expression by, approximately, 7- fold at 1 μM in a period of time of 72 and 96 hours, being most promising than the drug used in therapy, hydroxyurea (increase by 2.5-fold at 30 μM). In the part 2, it was synthesized 45 intermediates and 13 new final PROTACs with yields ranging from 30 to 65%. All compounds were evaluated towards HDAC 1-3 degradation and, in general, all of them presented selective degradation of HDAC-1. Compounds ARP-26, ARP-37 and ARP-49 presented the better degradation levels ranging from 41 to 60% against HDAC-1. DC50 values from compounds ARP-26 and ARP-49 were determined and shown approximately 50% of degradation at 2.5 μM. Therefore, in this work was possible to synthesize and characterize new HDAC inhibitors with interesting selectivity against HDAC- 1 and 2 with ability of induction of γ-globin in levels that exceed the results seen for the standard drug. It was also possible to synthesize and characterize new PROTACs with degradation selectivity against HDAC-1. (AU)

FAPESP's process: 18/19523-7 - Design, synthesis and pharmacological evaluation of hydroxyurea derivatives designed as histone deacetylase inhibitors for Sickle Cell Anemia
Grantee:Aline Renata Pavan
Support Opportunities: Scholarships in Brazil - Doctorate