Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia

• Grant number: 14/08247-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2014
• End date: June 10, 2019
• Field of knowledge: Health Sciences - Medicine
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: José Andrés Yunes
• Grantee: Nathalia Moreno Cury
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated scholarship(s): 17/14737-6 - Preclinical study of a colchicine binding site tubulin inhibitor with potent anti-leukemia activity and low toxicity, BE.EP.DR

Abstract

Acute leukemias (AL) are classified into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). ALL has an excellent cure rate with current treatments, but 20% of patients experience recurrence. AML has a cure rate of 60-70 % in children. The discovery of new drugs and drug targets can help improve these ratios. Inhibitors of DNA methyltransferases (DNMTs) represent a group of promising compounds for AL's treatment, since leukemic cells are characterized by changes in genomic methylation pattern. This project aims in vitro evaluation of a series of novel compounds, inhibitors of DNMTs and analogs to nanaomicina A, in AL. The effectiveness of the compounds will be evaluated by the inhibition assay of cell proliferation and survival. The compound with better activity in these trials will be selected for analysis of effects on cell cycle and apoptosis, along with the type of acute leukemia that shows better response to the compound. The compound's effect against normal cells will be assessed in bone marrow cells from healthy donors. Synergism between the test compound and chemotherapeutic agents used in AL's treatment will also be performed. The mechanism of action of the selected compound will be characterized by in vitro enzymatic assay of DNMT1, DNMT3a and DNMT3B inhibition. Moreover, we will characterize the changes in gene expression of AL's strains under treatment with the selected drug. Differentially expressed genes will be selected for analysis of methylation in their promoter regions. (AU)

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)

CANEVAROLO, RAFAEL RENATINO; DE SOUZA MELO, CAROLINA PEREIRA; CURY, NATHALIA MORENO; ARTICO, LEONARDO LUIZ; CORREA, JULIANA RONCHI; LAU, YANCA TONHASCA; MARIANO, SAMARA SOUSA; SUDALAGUNTA, PRANEETH REDDY; BRANDALISE, SILVIA REGINA; DE MATTOS ZERI, ANA CAROLINA; et al. Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines. FRONTIERS IN ONCOLOGY, v. 12, p. 18-pg., 2022-12-01. (12/11952-0, 14/08247-8, 08/10034-1, 09/04167-1, 17/02400-7, 17/03239-5)

CURY, NATHALIA MORENO; CAPITAO, REBECA MONIQUE; BORGES DE ALMEIDA, RENAN DO CANTO; ARTICO, LEONARDO LUIS; CORREA, JULIANA RONCHI; SIMAO DOS SANTOS, ERIC FRANCISCO; YUNES, JOSE ANDRES; DUARTE CORREIA, CARLOS ROQUE. Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 181, NOV 1 2019. (13/07600-3, 17/02400-7, 14/25770-6, 17/03239-5, 17/14737-6, 14/08247-8)

CURY, NATHALIA MORENO; MUEHLETHALER, TOBIAS; ALBERTONI LARANJEIRA, ANGELO BRUNELLI; CANEVAROLO, RAFAEL RENATINO; ZENATTI, PRISCILA PINI; LUCENA-AGELL, DANIEL; BARASOAIN, ISABEL; SONG, CHUNHUA; SUN, DONGXIAO; DOVAT, SINISA; et al. Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. ISCIENCE, v. 21, p. 95+, NOV 22 2019. (14/08247-8, 17/14737-6)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

CURY, Nathalia Moreno. Discovering the mechanism of action of new drugs using transcriptional profile analysis followed by preclinical studies in acute leukemias. 2019. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.