Narvaez, Ana J;
Ber, Suzan;
Crooks, Alex;
Emery, Amy;
Hardwick, Bryn;
Almeida, Estrella Guarino;
Huggins, David J;
... Venkitaraman, Ashok R; + view all
(2017)
Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS.
Cell Chemical Biology
, 24
(8)
1017-1028.e7.
10.1016/j.chembiol.2017.07.009.
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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.
| Type: | Article |
|---|---|
| Title: | Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.chembiol.2017.07.009 |
| Publisher version: | https://doi.org/10.1016/j.chembiol.2017.07.009 |
| Language: | English |
| Additional information: | © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | protein-protein interactions, PPI inhibitor, Polo-like kinase, Polo-box domain, PLK1, PLK4, mutant KRAS, c-MET, cancer therapy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10189182 |
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