ArticleACS medicinal chemistry letters2026
Targeting the H/KRAS α4-β6-α5 Allosteric Lobe with Macrocyclic Peptides.
Article in ACS medicinal chemistry letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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
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