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
• Start date: November 01, 2023
• End date: 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)

Scientific publications

(15)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PAVAN, ALINE RENATA; TERRONI, BARBARA; SANTOS, JEAN LEANDRO DOS. Endothelial dysfunction in Sickle Cell Disease: Strategies for the treatment. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 149, p. 11-pg., 2024-05-31. (23/05739-6, 18/19523-7)

JOAO, EMILIO EMILIO; LOPES, JULIANA ROMANO; GUEDES, BRUNA FERNANDA RODRIGUES; SANCHES, PAULO RICARDO DA SILVA; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO; SCARIM, CAUE BENITO. Advances in drug discovery of flavivirus NS2B-NS3pro serine protease inhibitors for the treatment of Dengue, Zika, and West Nile viruses. BIOORGANIC CHEMISTRY, v. 153, p. 22-pg., 2024-12-01. (23/05739-6)

BONJORNO, ANDRESSA FRANCIELLI; PAVAN, ALINE RENATA; FERNANDES, GUILHERME F. S.; SCARIM, CAUE BENITO; CASTAGNOLO, DANIELE; DOS SANTOS, JEAN LEANDRO. BacPROTACs targeting Clp protease: a promising strategy for anti-mycobacterial drug discovery. RONTIERS IN CHEMISTR, v. 12, p. 6-pg., 2024-01-31. (20/13279-7, 21/14973-7, 22/15844-9, 23/05739-6, 18/19523-7)

DE SOUZA, MATEUS MELLO; GINI, ANA LUISA RODRIGUEZ; MOURA, JHONNATHAN ALVES; SCARIM, CAUE BENITO; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Prodrug Approach as a Strategy to Enhance Drug Permeability. PHARMACEUTICALS, v. 18, n. 3, p. 46-pg., 2025-02-21. (23/14078-3, 23/05739-6)

FERNANDES, LIVIA DA ROCHA; LOPES, JULIANA ROMANO; BONJORNO, ANDRESSA FRANCIELLI; PRATES, JOAO LUCAS BRUNO; SCARIM, CAUE BENITO; DOS SANTOS, JEAN LEANDRO. The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors. Viruses-Basel, v. 15, n. 11, p. 34-pg., 2023-11-01. (20/13279-7, 23/05739-6)

DA CUNHA, PAMELA SOUZA TADA; GINI, ANA LUISA RODRIGUEZ; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO; SCARIM, CAUE BENITO. Recent Progress in Thiazole, Thiosemicarbazone, and Semicarbazone Derivatives as Antiparasitic Agents Against Trypanosomatids and Plasmodium spp.. Molecules, v. 30, n. 8, p. 42-pg., 2025-04-16. (23/05739-6)

GINI, ANA LUISA RODRIGUEZ; JOAO, EMILIO EMILIO; LOPES, JULIANA ROMANO; DA CUNHA, PAMELA SOUZA TADA; VELASQUEZ, ANGELA MARIA ARENAS; GRAMINHA, MARCIA APARECIDA SILVA; DOS SANTOS, JEAN LEANDRO; SCARIM, CAUE BENITO. Advances in Cysteine Protease B Inhibitors for Leishmaniasis Treatment. CURRENT DRUG TARGETS, v. N/A, p. 21-pg., 2024-09-27. (23/05739-6)

DELGADO, IVONE LEILA LIMA; SCARIM, CAUE BENITO; FERNANDES, FELIPE HUGO ALENCAR; BARBIERI, KARINA PEREIRA; POLESI, MARISA CAMPOS; PAVAN, ALINE RENATA; CHIBA, DIEGO EIDY; SALGADO, HERIDA REGINA NUNES; CARLOS, IRACILDA ZEPPONE; CORREA, MARCOS ANTONIO; et al. In vitro and In vivo Activity of a New N-Oxide Derivative for Acne Vulgaris Treatment. Medicinal Chemistry, v. N/A, p. 13-pg., 2024-07-31. (23/05739-6, 18/19523-7)

RODRIGUEZ GINI, ANA LUISA; SOUZA TADA DA CUNHA, PAMELA; JOAO, EMILIO EMILIO; MAN CHIN, CHUNG; DOS SANTOS, JEAN LEANDRO; SERRA, ESTEBAN CARLOS; BENITO SCARIM, CAUE. TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease. PHARMACEUTICALS, v. 18, n. 6, p. 63-pg., 2025-06-19. (23/05739-6)

GINI, ANA LUISA RODRIGUEZ; JOAO, EMILIO EMILIO; DOS SANTOS, JEAN LEANDRO; SCARIM, CAUE BENITO. Mannich Bases: Promising Scaffolds for the Treatment of Infectious Diseases. Current Medicinal Chemistry, v. N/A, p. 52-pg., 2025-03-10. (23/05739-6)

BONJORNO, ANDRESSA FRANCIELLI; DE SOUZA, MATEUS MELLO; GINI, ANA LUISA RODRIGUEZ; SCARIM, CAUE BENITO; DOS SANTOS, JEAN LEANDRO. Harnessing caseinolytic proteases ClpP1P2 for next-generation antimycobacterial agents: Mechanisms, challenges and opportunities. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 296, p. 16-pg., 2025-10-15. (24/03928-9, 23/05739-6, 23/14078-3)

LOPES, JULIANA ROMANO; MARIN-DETT, FREDDY HUMBERTO; SILVA, RITA ALEXANDRA MACHADO; CHELUCCI, RAFAEL CONSOLIN; SARAIVA, LUCILIA; SOUSA, MARIA EMILIA; FERREIRA, LEONARDO LUIZ GOMES; ANDRICOPULO, ADRIANO DEFINI; BARBUGLI, PAULA ABOUD; DOS SANTOS, JEAN LEANDRO. Design and Synthesis of Boronic Chalcones with Dual Anticancer and Anti-Inflammatory Activity. Molecules, v. 30, n. 14, p. 20-pg., 2025-07-19. (13/07600-3, 19/07574-9, 23/05739-6)

PRATES, JOAO LUCAS BRUNO; SILVA, SAMANTA DE MATOS; MEDINA-ALARCON, KAILA PETROLINA; DOS SANTOS, KELVIN SOUSA; BELIZARIO, JENYFFIE ARAUJO; LOPES, JULIANA ROMANO; MARIN-DETT, FREDDY HUMBERTO; CAMPOS, DEBORA LEITE; GIANNINI, MARIA JOSE SOARES MENDES; FUSCO-ALMEIDA, ANA MARISA; et al. Synthesis and Evaluation of Boron-Containing Heterocyclic Compounds with Antimicrobial and Anticancer Activities. Molecules, v. 30, n. 5, p. 27-pg., 2025-03-01. (22/15826-0, 19/07574-9, 23/01664-1, 23/03556-1, 23/05739-6)

PAVAN, ALINE R.; SMALLEY, JOSHUA P.; PATEL, URVASHI; PYTEL, WIKTORIA A.; DOS SANTOS, JEAN LEANDRO; COWLEY, SHAUN M.; SCHWABE, JOHN W. R.; HODGKINSON, JAMES T.. Cereblon-recruiting proteolysis targeting chimeras (PROTACs) can determine the selective degradation of HDAC1 over HDAC3. CHEMICAL COMMUNICATIONS, v. 60, n. 94, p. 4-pg., 2024-11-05. (21/10059-9, 23/05739-6, 18/19523-7)

BORESKI, DIOGO; SCHMID, VALENTINE FABIENNE; BOSQUESI, PRISCILA LONGHIN; DOS SANTOS, JEAN LEANDRO; SCARIM, CAUE BENITO; RESHETNIKOV, VIKTOR; CHIN, CHUNG MAN. Current Trends in Clinical Trials of Prodrugs. PHARMACEUTICALS, v. 18, n. 2, p. 37-pg., 2025-02-01. (23/08687-7, 23/05739-6, 23/15774-3)