Targeting the H/KRAS α4-β6-α5 Allosteric Lobe with Macrocyclic Peptides

Despite therapeutic advances against RAS mutations in cancer, acquired resistance frequently arises. Several secondary mutations at the binding sites effectively confer resistance to both Switch-II inhibitors and cyclophilin-A molecular glues. This underscores the need for RAS inhibitors that engage alternative binding pockets or operate through novel mechanisms. Here, we report the design of 10-mer macrocyclic peptides that mimic the FG-loop of the NS1 monobody, which targets the allosteric α4-α5-β6 surface of H/KRAS to disrupt RAS clustering and downstream signaling. These noncovalent inhibitors bind to H/KRAS with equivalent potencies, regardless of nucleotide state or the presence of oncogenic mutations (G12D, G12V, G13R, Q61K), and their binding site was confirmed by NMR and X-ray crystallography. Furthermore, covalent analogs targeting Cys118 were shown to label RAS in vitro and in complete cell lysates. Finally, we demonstrated that the key pharmacophores are connectable, providing a foundation for the development of smaller allosteric H/KRAS inhibitors.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2026-04-13
DOI
https://doi.org/10.1021/acsmedchemlett.6c00078
Primary Topic
Signaling Pathways in Disease
Type
article
Field-Weighted Citation Impact
0.00

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article

Targeting the H/KRAS α4-β6-α5 Allosteric Lobe with Macrocyclic Peptides

Anne Marinier, Hugo Lavoie, Pierre Thibault, Damien Garrido et al.
ACS Medicinal Chemistry Letters
Signaling Pathways in Disease
article

Targeting the H/KRAS α4-β6-α5 Allosteric Lobe with Macrocyclic Peptides

Anne Marinier, Hugo Lavoie, Pierre Thibault, Damien Garrido, Faraz Shaikh, Amal Wahhab, Michael J. Osborne, Doris A. Schuetz, Ryan C. Killoran, Éric Bonneil, Chang Hwa Jo, T. Arya, Matthew James Smith, Alexandre Beautrait, Kien Tran, Marc-André Poupart, Cédric Dicaire-Leduc, Marc Therrien
article en

Abstract

Despite therapeutic advances against RAS mutations in cancer, acquired resistance frequently arises. Several secondary mutations at the binding sites effectively confer resistance to both Switch-II inhibitors and cyclophilin-A molecular glues. This underscores the need for RAS inhibitors that engage alternative binding pockets or operate through novel mechanisms. Here, we report the design of 10-mer macrocyclic peptides that mimic the FG-loop of the NS1 monobody, which targets the allosteric α4-α5-β6 surface of H/KRAS to disrupt RAS clustering and downstream signaling. These noncovalent inhibitors bind to H/KRAS with equivalent potencies, regardless of nucleotide state or the presence of oncogenic mutations (G12D, G12V, G13R, Q61K), and their binding site was confirmed by NMR and X-ray crystallography. Furthermore, covalent analogs targeting Cys118 were shown to label RAS in vitro and in complete cell lysates. Finally, we demonstrated that the key pharmacophores are connectable, providing a foundation for the development of smaller allosteric H/KRAS inhibitors.

ACS Medicinal Chemistry Letters
Laboratoire de Mathématiques d'Orsay (FR), Institute for Research in Immunology and Cancer (CA), Département de Chimie Moléculaire (FR), Laboratoire de Biologie et Modélisation de la Cellule (FR), Pharmac (NZ), Université de Montréal (CA)
Canadian Cancer Society, Canada Research Chairs, Fonds de recherche du Québec, Canadian Institutes of Health Research
Good health and well-being
Openalex Percentile: Top 18%
Signaling Pathways in Disease
DOISourceOpenAlex
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