PLoS ONE (Jan 2015)

Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340).

  • Raoni Pais Siqueira,
  • Éverton de Almeida Alves Barbosa,
  • Marcelo Depólo Polêto,
  • Germanna Lima Righetto,
  • Thiago Vargas Seraphim,
  • Rafael Locatelli Salgado,
  • Joana Gasperazzo Ferreira,
  • Marcus Vinícius de Andrade Barros,
  • Leandro Licursi de Oliveira,
  • Angelo Brunelli Albertoni Laranjeira,
  • Márcia Rogéria Almeida,
  • Abelardo Silva Júnior,
  • Juliana Lopes Rangel Fietto,
  • Jörg Kobarg,
  • Eduardo Basílio de Oliveira,
  • Robson Ricardo Teixeira,
  • Júlio César Borges,
  • Jose Andrés Yunes,
  • Gustavo Costa Bressan

DOI
https://doi.org/10.1371/journal.pone.0134882
Journal volume & issue
Vol. 10, no. 8
p. e0134882

Abstract

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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.