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Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile
[Image: see text] KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460778/ https://www.ncbi.nlm.nih.gov/pubmed/36001446 http://dx.doi.org/10.1021/jacs.2c05377 |
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author | Zhang, Ziyang Morstein, Johannes Ecker, Andrew K. Guiley, Keelan Z. Shokat, Kevan M. |
author_facet | Zhang, Ziyang Morstein, Johannes Ecker, Andrew K. Guiley, Keelan Z. Shokat, Kevan M. |
author_sort | Zhang, Ziyang |
collection | PubMed |
description | [Image: see text] KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer. |
format | Online Article Text |
id | pubmed-9460778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-94607782022-09-10 Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile Zhang, Ziyang Morstein, Johannes Ecker, Andrew K. Guiley, Keelan Z. Shokat, Kevan M. J Am Chem Soc [Image: see text] KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer. American Chemical Society 2022-08-24 2022-09-07 /pmc/articles/PMC9460778/ /pubmed/36001446 http://dx.doi.org/10.1021/jacs.2c05377 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Zhang, Ziyang Morstein, Johannes Ecker, Andrew K. Guiley, Keelan Z. Shokat, Kevan M. Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile |
title | Chemoselective Covalent
Modification of K-Ras(G12R)
with a Small Molecule Electrophile |
title_full | Chemoselective Covalent
Modification of K-Ras(G12R)
with a Small Molecule Electrophile |
title_fullStr | Chemoselective Covalent
Modification of K-Ras(G12R)
with a Small Molecule Electrophile |
title_full_unstemmed | Chemoselective Covalent
Modification of K-Ras(G12R)
with a Small Molecule Electrophile |
title_short | Chemoselective Covalent
Modification of K-Ras(G12R)
with a Small Molecule Electrophile |
title_sort | chemoselective covalent
modification of k-ras(g12r)
with a small molecule electrophile |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460778/ https://www.ncbi.nlm.nih.gov/pubmed/36001446 http://dx.doi.org/10.1021/jacs.2c05377 |
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