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



Narvaez, Ana J, Ber, Suzan, Crooks, Alex, Emery, Amy, Hardwick, Bryn, Almeida, Estrella Guarino, Huggins, David J, Perera, David, Roberts-Thomson, Meredith, Azzarelli, Roberta
et al (show 9 more authors) (2017) Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. CELL CHEMICAL BIOLOGY, 24 (8). 1017-1028.E7.

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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.

Item Type: Article
Uncontrolled Keywords: Humans, Cell Cycle Proteins, Proto-Oncogene Proteins, Mitosis, Cell Survival, Molecular Structure, Protein Binding, Structure-Activity Relationship, Substrate Specificity, Dose-Response Relationship, Drug, Mutation, Proto-Oncogene Proteins p21(ras), Protein Interaction Domains and Motifs, Protein Serine-Threonine Kinases, Polo-Like Kinase 1
Depositing User: Symplectic Admin
Date Deposited: 24 Aug 2017 10:19
Last Modified: 02 Jan 2024 09:52
DOI: 10.1016/j.chembiol.2017.07.009
Open Access URL: http://www.sciencedirect.com/science/article/pii/S...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3009121