Autor(es)

de Miranda, Livia Bassani Lins ; Ferraz, Witor Ribeiro ; Lima, Keli ; Carlos, Jorge Antonio Elias Godoy ; Gatti, Fernando Moura ; Alves, Rodrigo Heleno ; Trossini, Gustavo Henrique Goulart ; Machado-Neto, Joao Agostinho

• Tipo de documento: Artigo Científico
• Fonte: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE; v. 8, n. 8, p. 11-pg., 2025-07-22.

Resumo

Acute myeloid leukemia (AML) remains a challenging hematological malignancy due to its genetic heterogeneity, high relapse rates, and limited therapeutic options for refractory cases. FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations are among the most frequent genetic alterations in AML, associated with poor prognosis and treatment resistance. In this study, we investigated the antileukemic potential of compound HI042, identified from a library of 78 molecules, focusing on its effects on FLT3-ITD-mutated AML models. HI042 selectively reduced the viability of FLT3-ITD-positive cell lines, induced apoptosis, disrupted cell cycle progression, and diminished the clonogenic potential. Chemoinformatics analysis revealed structural similarities between HI042 and retinoic acid analogues, known for their differentiation-inducing effects. Consistently, HI042 treatments increased the level of differentiation markers, including CD11b and transcription factors such as PU.1 and C/EBPs, particularly in MOLM-13 cells. Furthermore, combining HI042 with the FLT3 inhibitor quizartinib synergistically enhanced apoptosis and reduced cell proliferation. These findings highlight HI042's dual activity in inducing differentiation and apoptosis while synergizing with established therapies. Overall, HI042 emerges as a promising candidate for targeted therapies against FLT3-ITD-mutated AML, addressing a critical need for novel treatment strategies for this high-risk AML subgroup. (AU)

• Processo FAPESP: 21/11606-3 - Investigação dos efeitos antineoplásicos de novos inibidores de PIP4K2 e HDAC em neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 23/12246-6 - Avaliação dos efeitos antineoplásicos do inibidor multiquinase AD80 em neoplasias hematológicas com ativação constitutiva de vias tirosina-quinase
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 22/03316-8 - Investigação dos efeitos do inibidor multiquinase AD80 em neoplasias hematológicas com ativação constitutiva de vias tirosina-quinase
• Beneficiário: Lívia Bassani Lins de Miranda
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto