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Identification of Phosphate-Containing Compounds as New Inhibitors of 14-3-3/c-Abl Protein–Protein Interaction
journal contribution
posted on 2020-03-20, 17:42 authored by Leire Iralde-Lorente, Giusy Tassone, Letizia Clementi, Lorenzo Franci, Claire C Munier, Ylenia Cau, Mattia Mori, Mario Chiariello, Adriano Angelucci, Matthew W. D. Perry, Cecilia Pozzi, Stefano Mangani, Maurizio BottaThe 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 conclusion, our data suggest that 14-3-3σ targeting compounds
represent promising hits for further development of drugs against
c-Abl-dependent cancers.
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Keywords
c-Abl overexpressing cellspyridoxal phosphateNew Inhibitorsparent compoundsPrevious studiesSPR37- compound libraryFP assayc-Abl-dependent cancersantiproliferative activityCMLHs 27 fibroblastsX-ray crystallography screening programFP dataIMP analoguesinosine monophosphatetumor cellsleukemia cellsNMRPLPPhosphate-Containing Compoundsprotein amphipathic groovePPImyeloid leukemiaK -562 cellsphosphate-containing compounds
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