1. Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS.
- Author
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Narvaez AJ, Ber S, Crooks A, Emery A, Hardwick B, Guarino Almeida E, Huggins DJ, Perera D, Roberts-Thomson M, Azzarelli R, Hood FE, Prior IA, Walker DW, Boyce R, Boyle RG, Barker SP, Torrance CJ, McKenzie GJ, and Venkitaraman AR
- Subjects
- Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins chemistry, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Mitosis, Molecular Structure, Protein Binding, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases chemistry, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins chemistry, Structure-Activity Relationship, Substrate Specificity, Polo-Like Kinase 1, Cell Cycle Proteins metabolism, Mutation, Protein Interaction Domains and Motifs drug effects, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism
- 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., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2017
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