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Type: Artigo
Title: Potential antileukemia effect and structural analyses of Srpk inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)
Author: Siqueira, Raoni Pais
Barbosa, Everton de Almeida Alves
Poleto, Marcelo Depolo
Righetto, Germanna Lima
Seraphim, Thiago Vargas
Salgado, Rafael Locatelli
Ferreira, Joana Gasperazzo
de Andrade Barros, Marcus Vincius
de Oliveira, Leandro Licursi
Albertoni Laranjeira, Angelo Brunelli
Almeida, Marcia Rogeria
Silva Junior, Abelardo
Rangel Fietto, Juliana Lopes
Kobarg, Joerg
de Oliveira, Eduardo Basilio
Teixeira, Robson Ricardo
Borges, Julio Cesar
Yunes, Jose Andres
Bressan, Gustavo Costa
Abstract: Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates
Subject: Processamento de RNA
Country: Estados Unidos
Editor: Public Library of Science
Rights: Aberto
Identifier DOI: 10.1371/journal.pone.0134882
Date Issue: 2015
Appears in Collections:IB - Artigos e Outros Documentos

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