Potential antileukemia effect and structural analyses of Srpk inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria...
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria Almeida, Abelardo Silva Junior, Juliana Lopes Rangel Fietto, Joerg Kobarg, Eduardo Basilio de Oliveira, Robson Ricardo Teixeira, Julio Cesar Borges, Jose Andres Yunes, Gustavo Costa Bressan
ARTIGO
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Agradecimentos: Fundacao Arthur Bernardes (FUNARBE)
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...
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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
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CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ
485011/2012-3; 552459/2011-9
COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES
FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAIS - FAPEMIG
CBB-APQ-01637-13
Aberto
Potential antileukemia effect and structural analyses of Srpk inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria...
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria Almeida, Abelardo Silva Junior, Juliana Lopes Rangel Fietto, Joerg Kobarg, Eduardo Basilio de Oliveira, Robson Ricardo Teixeira, Julio Cesar Borges, Jose Andres Yunes, Gustavo Costa Bressan
Potential antileukemia effect and structural analyses of Srpk inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria...
Raoni Pais Siqueira, Everton de Almeida Alves Barbosa, Marcelo Depolo Poleto, Germanna Lima Righetto, Thiago Vargas Seraphim, Rafael Locatelli Salgado, Joana Gasperazzo Ferreira, Marcus Vincius de Andrade Barros, Leandro Licursi de Oliveira, Angelo Brunelli Albertoni Laranjeira, Marcia Rogeria Almeida, Abelardo Silva Junior, Juliana Lopes Rangel Fietto, Joerg Kobarg, Eduardo Basilio de Oliveira, Robson Ricardo Teixeira, Julio Cesar Borges, Jose Andres Yunes, Gustavo Costa Bressan
Fontes
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PLoS one Vol. 10, no. 8 (Aug., 2015), n. art. e0134882 |