ArticleChemical science2021
Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- Engineered subtilisin protease degrades active KRAS in cancer cells leading to differential cell targeting.Research square · 2026Article
- Similarity-Enhanced Representation Learning of Non-Canonical Amino Acids for Therapeutic Peptide Modeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The AUTACE That Degrades KRAS and Engages CD8Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting the Undruggable: Deep Learning-Driven Design of Peptide Therapeutics in Cancer.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V.Biochemistry · 2026Article
- Engineered subtilisin protease degrades active KRAS in cancer cells, leading to differential cell targeting.bioRxiv : the preprint server for biology · 2026Article
- Affinity selection-mass spectrometry with linearizable macrocyclic peptide libraries.Science advances · 2025Article
- Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery.Frontiers in chemistry · 2025Review
- Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.Chemical reviews · 2024Review
- Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists.Nature communications · 2024Article
- Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer.Journal of medicinal chemistry · 2023Article
- CRISPR-mediated reversion of oncogenic KRAS mutation results in increased proliferation and reveals independent roles of Ras and mTORC2 in the migration of A549 lung cancer cells.Molecular biology of the cell · 2023Article
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- New prospectives on treatment opportunities in RASopathies.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology.Journal of medicinal chemistry · 2022Article
- Utilization of macrocyclic peptides to target protein-protein interactions in cancer.Frontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
33 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure-activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight - the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in an
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.