Nifuroxazide as JAK2 inhibitor: A binding mode proposal and Hel cell proliferation assay

Autor(es)

da Costa, Marcela Oliveira Legramanti ^[1] ; Pavani, Thais Fernanda Amorim ^[1] ; Scott, Ana Ligia ^[2] ; Ramos, Debora Felicia Vieira ^{[2, 3]} ; Lazarini, Mariana ^[3] ; Rando, Daniela Goncales Galasse ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Grp Pesquisas Quim Farmaceut, Campus Diadema, Diadema - Brazil

^[2] Univ Fed ABC, Lab Biol Computac & Bioinformat, Santo Andre, SP - Brazil

^[3] Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Campus Diadema, Diadema - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 162, JUL 1 2021.
• Citações Web of Science: 0

Resumo

Nifuroxazide has been employed as an anti-diarrheic agent since 1966, but in the last decade has brought to the research spotlight again due to its recently described antitumoral activity through the JAK2 inhibitory potential. Since 2008, more than 70 papers have been published about the issue and more are expected to the following years. Herein we discuss the findings of molecular modelling studies which were performed to elucidate the potential binding mode of this drug into the JAK2 ATP recognition site and also into the allosteric region near the catalytic site. Molecular modelling followed by dynamics simulations indicated the NFZ could bind at both sites, such as a Type II kinase inhibitor since residues from both ATP and modulatory site would exhibit contacts with the drug when in a stable complex. Synthesis of NFZ and its sulfur bioisosteric analogue GPQF-63 were performed and experimental assays against HEL cells indicate the potential of NFZ and, mainly of its analogue GPQF-63 in acting as inhibitors of cell growth. HEL-cells present the JAK2 V617F mutation which leads to an enhanced JAK/STAT pathway and they have never been tested by the NFZ activity before. A mechanistic approach was also performed and revealed that both compounds induce cell apoptosis.Taken together, both the theoretical and experimental approaches point out the N-acylhydrazones as good starting points in the search for JAK2 modulatory small molecules which could then, be studied as promising leads toward new alternatives to control the JAK-STAT pathway related pathologies. This is the first study, as far as we have known, to propose a potential binding mode for NFZ as well as reporting the activity of this drug against HEL cells, which are a usual cellular model to human erythroleukemia and other myeloproliferative diseases. (AU)

• Processo FAPESP: 19/26686-2 - Catepsina B1 de Schistosoma mansoni: design e síntese racional de potenciais inibidores
• Beneficiário: Daniela Goncales Galasse Rando
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/01875-0 - Síntese paralela, screening in vitro e estudos de relação estrutura-atividade de nitroderivados ativos contra patógenos infectantes de macrófagos: Mycobacterium tuberculosis formas NRP e Leishmania sp
• Beneficiário: Daniela Goncales Galasse Rando
• Modalidade de apoio: Auxílio à Pesquisa - Regular