Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. Issue 8 (17th August 2017)

• Record Type: Journal Article
• Authors: Narvaez, Ana J.; Ber, Suzan; Crooks, Alex; Emery, Amy; Hardwick, Bryn; Guarino Almeida, Estrella; Huggins, David J.; Perera, David; Roberts-Thomson, Meredith; Azzarelli, Roberta; Hood, Fiona E.; Prior, Ian A.; Walker, David W.; Boyce, Richard; Boyle, Robert G.; Barker, Samuel P.; Torrance, Christopher J.; McKenzie, Grahame J.; Venkitaraman, Ashok R.
• Is Part Of: Cell chemical biology. Volume 24:Issue 8(2017)
• Page Start: 1017
• Page End: 1028.e7
• Publication Date: 2017-08-17
• Subjects: protein-protein interactions -- PPI inhibitor -- Polo-like kinase -- Polo-box domain -- PLK1 -- PLK4 -- mutant KRAS -- c-MET -- cancer therapy; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.07.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Poloppins target the PBD of human PLKs causing mitotic death in KRAS-mutant cells Depletion of PLK1 or PLK4 recapitulates the cellular effects of Poloppins Poloppins reduce drug resistance in vitro, and act against KRAS-mutant xenografts Poloppins sensitize KRAS-mutant cells to clinically used c-MET inhibitors Abstract : Narvaez et al. report the development of Poloppins, compounds that target the protein-protein interactions of human Polo-like kinases via their Polo-box domain, in monotherapeutic or combination strategies to treat KRAS-mutant cancers.