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


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.

DOI: 10.1371/journal.pone.0134882

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@inproceedings{Siqueira2015PotentialAE, title={Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)}, author={Raoni Pais Siqueira and {\'E}verton de Almeida Alves Barbosa and Marcelo Dep{\'o}lo Pol{\^e}to and Germanna Lima Righetto and Thiago Vargas Seraphim and Rafael Locatelli Salgado and Joana Gasperazzo Ferreira and Marcus Vin{\'i}cius de Andrade Barros and Leandro Licursi de Oliveira and Angelo Brunelli Albertoni Laranjeira and M{\'a}rcia Rog{\'e}ria de Almeida and Abelardo Silva J{\'u}nior and Juliana Lopes Rangel Fietto and J{\"{o}rg Kobarg and Eduardo Bas{\'i}lio de Oliveira and R{\'o}bson Ricardo Teixeira and J{\'u}lio C{\'e}sar Borges and Jos{\'e} Andr{\'e}s Yunes and Gustavo Costa Bressan and Emanuele Buratti}, booktitle={PloS one}, year={2015} }