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Tipo: Artigo
Título: Potential antileukemia effect and structural analyses of SRPK inhibition by N-(2- (Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl) isonicotinamide (SRPIN340)
Autor(es): Siqueira, Raoni Pais
Barbosa, Éverton de Almeida Alves
Polêto, Marcelo Depólo
Righetto, Germanna Lima
Seraphim, Thiago Vargas
Salgado, Rafael Locatelli
Ferreira, Joana Gasperazzo
Oliveira, Leandro Licursi de
Laranjeira, Angelo Brunelli Albertoni
Almeida, Márcia Rogéria
Fietto, Juliana Lopes Rangel
Kobarg, Jörg
Oliveira, Eduardo Basílio de
Teixeira, Robson Ricardo
Borges, Júlio César
Silva Júnior, Abelardo
Bressan, Gustavo Costa
et al.
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.
Palavras-chave: Potential antileukemia
2- (Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)
Editor: Plos One
Tipo de Acesso: Open Access
Data do documento: 8-Abr-2014
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