Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies

• Grant number: 21/11606-3
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2022
• End date: May 31, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: João Agostinho Machado Neto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Leticia Veras Costa Lotufo ; Roberto Parise Filho

Abstract

Hematopoiesis is a highly organized hierarchical process responsible for the production of erythrocytes, leukocytes and platelets. In neoplastic processes, there is a change in regulatory mechanisms, leading to the replacement of healthy cells by neoplastic cells and consequent suppression of normal hematopoiesis. Despite great advances in understanding the biology of hematologic malignancies in recent years, therapeutic options remain limited. In this context, (i) PIP4K2 family proteins may play a role in the pathogenesis and prognosis of acute leukemias and (ii) the increased activity of HDACs promotes chromatin compaction and repression of the expression of specific genes contributing to the phenotype malignant. Thus, the present research project seeks to act on two distinct fronts in an attempt to expand the antineoplastic arsenal against these diseases. The first front of the study is the characterization of the cellular and molecular effects of a novel pharmacological inhibitor of PIP4K2 in preclinical models of human leukemias. The second front of study is the search for novel HDAC inhibitors with greater potency and selectivity for advances in the pharmacology of epigenetic modulators, and new compounds synthesized in collaboration at our institution will be tested. Our expectation is to generate proof-of-concept in cellular and molecular pharmacology and provide opportunities for the development of new therapies for hematologic malignancies. (AU)

Scientific publications

(9)

(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)

MORAES, VIVIAN W. R.; SANTOS, VIVIAN M.; SUAREZ, ELOAH R.; FERRAZ, LETICIA S.; LOPES, RAYSSA DE MELLO; MOGNOL, GIULIANA P.; CAMPEIRO, JOANA D.; MACHADO-NETO, JOAO A.; NASCIMENTO, FABIO D.; HAYASHI, MIRIAN A. F.; et al. Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells. LIFE-BASEL, v. 12, n. 10, p. 20-pg., 2022-10-01. (20/01107-7, 16/07367-5, 18/25747-5, 06/00995-9, 17/02413-1, 21/11606-3)

DE ALMEIDA, LARISSA COSTA; CALIL, FELIPE ANTUNES; MORENO, NATALIA CESTARI; REZENDE-TEIXEIRA, PAULA; DE MORAES, LUIZ ALBERTO BERALDO; JIMENEZ, PAULA CHRISTINE; MENCK, CARLOS FREDERICO MARTINS; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chemico-Biological Interactions, v. 371, p. 10-pg., 2023-01-14. (17/24993-0, 18/17595-0, 14/50926-0, 19/23864-7, 21/11606-3, 19/19435-3, 15/17177-6)

LINS DE MIRANDA, LIVIA BASSANI; LIMA, KELI; COELHO-SILVA, JUAN LUIZ; TRAINA, FABIOLA; KOBAYASHI, SUSUMU S.; MACHADO-NETO, JOAO AGOSTINHO. NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells. SCIENTIFIC REPORTS, v. 12, n. 1, p. 11-pg., 2022-10-12. (19/23864-7, 20/12748-3, 21/11606-3)

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)

MACHADO-NETO, JOAO AGOSTINHO; DO NASCIMENTO, MARIANE CRISTINA; GARNIQUE, ANALI DEL MILAGRO BERNABE; LIMA, KELI. Data mining in acute myeloid leukemia: identification of disease biomarkers, prognostic factors, novel targets, and potential drugs. TRANSLATIONAL CANCER RESEARCH, v. N/A, p. 4-pg., 2023-08-15. (21/11606-3, 20/12842-0)

VICARI, HUGO PASSOS; LIMA, KELI; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms. CANCERS, v. 14, n. 24, p. 15-pg., 2022-12-01. (21/01460-1, 19/23864-7, 19/01700-2, 21/11606-3)

DE ALMEIDA, LARISSA COSTA; CARLOS, JORGE ANTONIO ELIAS GODOY; REZENDE-TEIXEIRA, PAULA; MACHADO-NETO, JOAO AGOSRINHO; COSTA-LOTUFO, LETICIA VERAS. AD80, a multikinase inhibitor, as a potential drug candidate for colorectal cancer therapy. Life Sciences, v. 308, p. 9-pg., 2022-09-02. (18/19372-9, 17/24993-0, 18/17595-0, 19/23864-7, 21/11606-3, 15/17177-6)

LIMA, KELI; PEREIRA-MARTINS, DIEGO ANTONIO; LINS DE MIRANDA, LIVIA BASSANI; COELHO-SILVA, JUAN LUIZ; LEANDRO, GIOVANA DA SILVA; WEINHAUSER, ISABEL; CAVAGLIERI, RITA DE CASSIA; LEAL, ALINE DE MEDEIROS; DA SILVA, WELLINGTON FERNANDES; ALENCAR DE LIMA LANGE, ANA PAULA; et al. The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy. BLOOD CANCER JOURNAL, v. 12, n. 11, p. 11-pg., 2022-11-09. (15/09228-0, 20/12842-0, 19/23864-7, 21/11606-3, 17/23117-1)

LIMA, KELI; DE MIRANDA, LIVIA BASSANI LINS; GARNIQUE, ANALI DEL MILAGRO BERNABE; DE ALMEIDA, BRUNA OLIVEIRA; DO NASCIMENTO, MARIANE CRISTINA; ALCANTARA, GUILHERME AUGUSTO SOUSA; MACHADO-SANTELLI, GLAUCIA MARIA; REGO, EDUARDO MAGALHAES; MACHADO-NETO, JOAO AGOSTINHO. The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells. CANCERS, v. 15, n. 15, p. 14-pg., 2023-08-01. (19/23864-7, 21/11606-3, 20/12842-0, 22/03316-8, 19/25421-5)