Identification of Phosphate-Containing Compounds as New Inhibitors of 14-3-3/c-Abl Protein-Protein Interaction.

ACS Chemical Biology
Leire Iralde-LorenteMaurizio Botta

Abstract

The 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukemia cells. Through an X-ray crystallography screening program, we have identified two phosphate-containing compounds, inosine monophosphate (IMP) and pyridoxal phosphate (PLP), as binders of human 14-3-3σ, by targeting the protein amphipathic groove. Interestingly, they also act as weak inhibitors of the 14-3-3/c-Abl PPI, demonstrated by NMR, SPR, and FP data. A 37-compound library of PLP and IMP analogues was investigated using a FP assay, leading to the identification of three further molecules acting as weak inhibitors of the 14-3-3/c-Abl complex formation. The antiproliferative activity of IMP, PLP, and the three derivatives was tested against K-562 cells, showing that the parent compounds had the most pronounced effect on tumor cells. PLP and IMP were also effective in promoting the c-Abl nuclear translocation in c-Abl overexpressing cells. Further, these compounds demonstrated low cytotoxicity on human Hs27 fibroblasts. In c...Continue Reading

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Citations

Dec 9, 2020·Pharmaceuticals·Ghazi Aljabal, Beow Keat Yap
Oct 15, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Claire C MunierMatthew W D Perry
Feb 2, 2021·Trends in Pharmacological Sciences·F Sanders Pair, Talene A Yacoubian
Sep 21, 2020·Clinica Chimica Acta; International Journal of Clinical Chemistry·Yun HuangWeiguo Huang
Nov 4, 2020·Journal of Chemical Information and Modeling·Alice BalloneMattia Mori

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