Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS
Guarino Almeida, E
Cell Chemical Biology
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Narvaez, A., Ber, S., Crooks, A., Emery, A., Hardwick, B., Guarino Almeida, E., Huggins, D., et al. (2017). Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. Cell Chemical Biology, 24 (8), 1017-1028.e7. https://doi.org/10.1016/j.chembiol.2017.07.009
Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis. PLK1 or PLK4 depletion recapitulates these cellular effects, as does PBD overexpression, corroborating Poloppin's mechanism of action. An optimized analog with favorable pharmacokinetics, Poloppin-II, is effective against KRAS-expressing cancer xenografts. Poloppin resistance develops less readily than to an ATP-competitive PLK1 inhibitor; moreover, cross-sensitivity persists. Poloppin sensitizes mutant KRAS-expressing cells to clinical inhibitors of c-MET, opening opportunities for combination therapy. Our findings exemplify the utility of small molecules modulating the protein-protein interactions of PLKs to therapeutically target mutant KRAS-expressing cancers.
PLK1, PLK4, PPI inhibitor, Polo-box domain, Polo-like kinase, c-MET, cancer therapy, mutant KRAS, protein-protein interactions
All authors, except R.A., D.W.W., R.B., R.G.B., F.E.H., I.A.P., S.P.B., and C.J.T., were supported by Medical Research Council program grants MC_UU_12022/1 and MC_UU_12022/8 to A.R.V. North West Cancer Research supported I.A.P. and F.E.H. Innovate UK funded the development of Poloppin-II by PhoreMost Ltd. (Biomedical Catalyst grant no. 102140). R.A. was supported by MRC research grant MR/K018329/1 and the Rosetrees Trust.
External DOI: https://doi.org/10.1016/j.chembiol.2017.07.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267376
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