srpin340 and Leukemia

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Leukemia; Niacinamide; Piperidines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Vincristine

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.

Topics: Antineoplastic Agents; Apoptosis; Binding Sites; Blotting, Western; Cell Survival; Cells, Cultured; Gene Expression Regulation, Leukemic; HeLa Cells; HL-60 Cells; Humans; Jurkat Cells; K562 Cells; Leukemia; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Niacinamide; Piperidines; Protein Binding; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Fluorescence