Claringbold, Bini;
Vance, Steven;
Paul, Alexandra R;
Williamson, James;
Garrett, Michelle D;
Serpell, Christopher J;
(2024)
Sequence-defined phosphoestamers for selective inhibition of the KRASG12D/RAF1 interaction.
Chemical Science
, 16
pp. 113-123.
10.1039/d4sc07218a.
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Abstract
RAS proteins are the most frequently mutated in cancer, yet they have proved extremely difficult to target in drug discovery, largely because interfering with the interaction of RAS with its downstream effectors comes up against the challenge of protein-protein interactions (PPIs). Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules with the size required to address entire PPI surfaces. We have adapted the phosphoramidite chemistry of oligonucleotide synthesis to produce a library of nearly one million non-nucleosidic oligophosphoester sequences (phosphoestamers) composed of units taken from synthetic supramolecular chemistry, and used a fluorescent-activated bead sorting (FABS) process to select those that inhibit the interaction between KRASG12D (the most prevalent, and undrugged, RAS mutant) and RAF, a downstream effector of RAS that drives cell proliferation. Hits were identified using tandem mass spectrometry, and orthogonal validation showed effective inhibition of KRASG12D with IC50 values as low as 25 nM, and excellent selectivity over the wild type form. These findings have the potential to lead to new drugs that target mutant RAS-driven cancers, and provide proof-of-principle for the phosphoestamer chemical platform against PPIs in general - opening up new possibilities in neurodegenerative disease, viral infection, and many more conditions.
| Type: | Article |
|---|---|
| Title: | Sequence-defined phosphoestamers for selective inhibition of the KRASG12D/RAF1 interaction |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1039/d4sc07218a |
| Publisher version: | https://doi.org/10.1039/d4sc07218a |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. |
| 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204796 |
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