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Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia

Grant number: 14/08247-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2014
Effective date (End): June 10, 2019
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:José Andrés Yunes
Grantee:Nathalia Moreno Cury
Home 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)

Filed patent(s) as a result of this research project

ACIL-HIDRAZONAS COMO PROTÓTIPO DE NOVOS FÁRMACOS PARA LEUCEMIA LINFÓIDE AGUDA (LLA) PI1107312-8 - Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Taisa Regina Stumpf; Paulo César Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; Rosendo A. Yunes; Ângelo Bruneli Albertoni Laranjeira - November 2011, 25

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF CA2869807 - Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Taisa Regina Stumpf; Paulo César Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; Rosendo A. Yunes; Ângelo Bruneli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF CN201280063518 - Alessandra Mascarello ; André Bortolini Silveira ; Carolina Pereira de Souza Melo ; José Andres Yunes ; Louise Domeneghini Chiaradia ; Paulo Cesar Leal ; Rafael Renatino Canevarolo ; Ricardo José Nunes ; Rosendo Augusto Yunes ; Taisa Regina Stumpf ; Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF EP20120851308 - Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF JP2014542646 - Alessandra Mascarello ; André Bortolini Silveira ; Carolina Pereira de Souza Melo ; José Andres Yunes ; Louise Domeneghini Chiaradia ; Paulo Cesar Leal ; Rafael Renatino Canevarolo ; Ricardo José Nunes ; Rosendo Augusto Yunes ; Taisa Regina Stumpf ; Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF PCT/BR2012/000480 - Alessandra Mascarello ; André Bortolini Silveira ; Carolina Pereira de Souza Melo ; José Andres Yunes ; Louise Domeneghini Chiaradia ; Paulo Cesar Leal ; Rafael Renatino Canevarolo ; Ricardo José Nunes ; Rosendo Augusto Yunes ; Taisa Regina Stumpf ; Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF RU2014125519 - Alessandra Mascarello ; André Bortolini Silveira ; Carolina Pereira de Souza Melo ; José Andres Yunes ; Louise Domeneghini Chiaradia ; Paulo Cesar Leal ; Rafael Renatino Canevarolo ; Ricardo José Nunes ; Rosendo Augusto Yunes ; Taisa Regina Stumpf ; Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26

ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF US14/360,279 - Universidade Federal de Santa Catarina (UFSC) . Ricardo José Nunes; Alessandra Mascarello; Rosendo Augusto Yunes; Taisa Regina Stumpf; Paulo Cesar Leal; José Andres Yunes; Carolina Pereira de Souza Melo; Rafael Renatino Canevarolo; Louise Domeneghini Chiaradia; André Bortolini Silveira; Anqelo Brunelli Albertoni Laranjeira - November 2012, 26