title: Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340).
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.
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Raoni Pais
authors.initials: RP
authors.lastname: Siqueira
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Éverton de Almeida Alves
authors.initials: Éde A
authors.lastname: Barbosa
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Marcelo Depólo
authors.initials: MD
authors.lastname: Polêto
authors.affiliation: Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brasil.
authors.forename: Germanna Lima
authors.initials: GL
authors.lastname: Righetto
authors.affiliation: Instituto de Química, Universidade de São Paulo, São Carlos, São Paulo, Brasil.
authors.forename: Thiago Vargas
authors.initials: TV
authors.lastname: Seraphim
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Rafael Locatelli
authors.initials: RL
authors.lastname: Salgado
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Joana Gasperazzo
authors.initials: JG
authors.lastname: Ferreira
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Marcus Vinícius de Andrade
authors.initials: MV
authors.lastname: Barros
authors.affiliation: Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Leandro Licursi
authors.initials: LL
authors.lastname: de Oliveira
authors.affiliation: Centro Infantil Boldrini, Campinas, São Paulo, Brasil.
authors.forename: Angelo Brunelli Albertoni
authors.initials: AB
authors.lastname: Laranjeira
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Márcia Rogéria
authors.initials: MR
authors.lastname: Almeida
authors.affiliation: Departamento de Veterinária, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Abelardo Silva
authors.initials: AS
authors.lastname: Júnior
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Juliana Lopes Rangel
authors.initials: JL
authors.lastname: Fietto
authors.affiliation: Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, São Paulo, Brasil.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kobarg
authors.affiliation: Departamento de Engenharia de Alimentos, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Eduardo Basílio
authors.initials: EB
authors.lastname: de Oliveira
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Robson Ricardo
authors.initials: RR
authors.lastname: Teixeira
authors.affiliation: Instituto de Química, Universidade de São Paulo, São Carlos, São Paulo, Brasil.
authors.forename: Júlio César
authors.initials: JC
authors.lastname: Borges
authors.affiliation: Centro Infantil Boldrini, Campinas, São Paulo, Brasil.
authors.forename: Jose Andrés
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brasil.
authors.forename: Gustavo Costa
authors.initials: GC
authors.lastname: Bressan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; C584061:SRPIN340; D009536:Niacinamide; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases; C110522:SRPK2 protein, human