Identification of phosphate-containing compounds as new inhibitors of 14-3-3/c-Abl protein-protein interaction

DOI: 10.1021/acschembio.0c00039

Authors: Leire Iralde-lorente (Università degli Studi di Siena) , Giusy Tassone (Università degli Studi di Siena) , Letizia Clementi (University of L'Aquila) , Lorenzo Franci (la Prevenzione e la Rete Oncologica (ISPRO); Università degli Studi di Siena; Consiglio Nazionale delle Ricerche) , Claire C Munier (AstraZeneca) , Ylenia Cau (Università degli Studi di Siena) , Mattia Mori (Università degli Studi di Siena) , Mario Chiariello (Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO); Consiglio Nazionale delle Ricerche) , Adriano Angelucci (University of L'Aquila) , Matthew W. D. Perry (AstraZeneca) , Cecilia Pozzi (Università degli Studi di Siena) , Stefano Mangani (Università degli Studi di Siena) , Maurizio Botta (Università degli Studi di Siena)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: March 2020

Abstract: The 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukaemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukaemia 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 tumour 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.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: ID30-B at ESRF