Characterization of the activity of potential histone deacetylase (HDAC) inhibitors in preclinical models of hematologic malignancies

• Grant number: 21/06138-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2022
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Jorge Antonio Elias Godoy Carlos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hematopoiesis is a highly organized process responsible for the production of erythrocytes, leukocytes, and platelets, which in neoplastic processes undergo changes in regulatory processes leading to the replacement of healthy cells by neoplastic cells, observing the leukemic phenotype. Leukemias can be acute or chronic and affect myeloid and/or lymphoid progenitors and their treatment in some cases proves to be ineffective, bringing the need for new therapeutic options. In this context, epigenetic alterations have become the target of studies in various types of cancer, especially in hematological ones. Observing its relationship with carcinogenic processes, alterations in histone acetylation/deacetylation promoted by enzymes called histone deacetylases (HDAC), it has been strongly shown to be possible pharmacological targets since these processes can lead to relaxation or increased condensation of the genetic material, respectively, then promoting post-translational changes related to processes of apoptosis, differentiation, DNA repair and others related to carcinogenesis. The use of compounds with potential inhibitory activity of these enzymes has been showing promising results in preclinical studies and the search for new compounds that present greater potency and selectivity is necessary. Previously, in a collaborative study, a total of 15 compounds with potential HDAC inhibitor activity were developed, which showed selective antileukemia activity in preliminary trials, and further studies are needed to elucidate the mechanism of action. Taking into account the initial results compared with drugs of the same class found in the literature, we believe that these compounds are promising candidates for a more robust preclinical evaluation contemplated by the objectives of this research project.

Scientific publications

(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)

MACHADO-NETO, JOAO AGOSTINHO; CARLOS, JORGE ANTONIO ELIAS GODOY; LIMA, KELI. miRNAs as prognostic predictors in acute myeloid leukemia. TRANSLATIONAL CANCER RESEARCH, v. N/A, p. 4-pg., 2023-06-25. (21/06138-0, 21/11606-3, 20/12842-0)

CARLOS, JORGE ANTONIO ELIAS GODOY; TAVARES, MAURICIO TEMOTHEO; LIMA, KELI; DE ALMEIDA, LARISSA COSTA; WAITMAN, KAROLINE DE BARROS; COSTA-LOTUFO, LETICIA VERAS; PARISE-FILHO, ROBERTO; MACHADO-NETO, JOAO AGOSTINHO. Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors. CELL DEATH DISCOVERY, v. 11, n. 1, p. 11-pg., 2025-04-06. (21/06138-0, 21/08260-8, 24/07723-2, 21/11606-3, 23/12246-6)

CARLOS, JORGE ANTONIO ELIAS GODOY; LIMA, KELI; REGO, EDUARDO MAGALHA; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells. Hematology, Transfusion and Cell Therapy, v. 46, p. 11-pg., 2024-12-19. (21/11606-3, 20/12842-0, 21/06138-0)