2. Academic Validation
  3. Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS

Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS

  • Cell Chem Biol. 2017 Aug 17;24(8):1017-1028.e7. doi: 10.1016/j.chembiol.2017.07.009.
Ana J Narvaez 1,  Suzan Ber 1,  Alex Crooks 1,  Amy Emery 1,  Bryn Hardwick 1,  Estrella Guarino Almeida 1,  David J Huggins 2,  David Perera 1,  Meredith Roberts-Thomson 1,  Roberta Azzarelli 3,  Fiona E Hood 4,  Ian A Prior 4,  David W Walker 5,  Richard Boyce 5,  Robert G Boyle 5,  Samuel P Barker 6,  Christopher J Torrance 6,  Grahame J McKenzie 7,  Ashok R Venkitaraman 8
Affiliations

Affiliations

  • 1 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
  • 2 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; University of Cambridge, Theory of Condensed Matter Group, Cavendish Laboratory, 19 J J Thomson Avenue, Cambridge CB3 0HE, UK.
  • 3 Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
  • 4 Division of Cellular and Molecular Physiology, Crown Street, University of Liverpool, Liverpool L69 3BX, UK.
  • 5 Sentinel Oncology Ltd., Cambridge Science Park, Milton Road, Cambridge CB4 0EY, UK.
  • 6 PhoreMost Ltd., Babraham Research Campus, Cambridge CB22 3AT, UK.
  • 7 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK; PhoreMost Ltd., Babraham Research Campus, Cambridge CB22 3AT, UK.
  • 8 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK. Electronic address: arv22@mrc-cu.cam.ac.uk.
PMID: 28807782 DOI: 10.1016/j.chembiol.2017.07.009
Abstract

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.

Keywords

PLK1; PLK4; PPI inhibitor; Polo-box domain; Polo-like kinase; c-MET; cancer therapy; mutant KRAS; protein-protein interactions.

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