ArticleProceedings of the National Academy of Sciences of the United States of America2023
Exploring switch II pocket conformation of KRAS(G12D) with mutant-selective monobody inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Targeting KRASFrontiers in oncology · 2026Pooled it
- Neoantigen cancer vaccines for gastrointestinal tumors: opportunities and challenges.MedScience · 2026Review
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- Natural Products in Cancer Research: Mechanistic Advances, Translational Challenges, and the Emerging Role of Chilean Biodiversity.Molecules (Basel, Switzerland) · 2026Review
- Structural and Energetic Determinants of Monobody Recognition of Oncogenic KRAS Variants.bioRxiv : the preprint server for biology · 2026Article
- Current advances in immunotherapy for KRAS-Mutant pancreatic cancer.Clinical and experimental medicine · 2026Review
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- Recent breakthroughs in understanding the allosteric features of Ras GTPases and their effector and regulatory protein interactions, enabling drug design.Current opinion in structural biology · 2026Review
- Targeting KRAS G12D: Advances in Inhibitor Design.Thoracic cancer · 2025Review
- A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.Molecular oncology · 2025Article
- A Hit Prioritization Strategy for Compound Library Screening Using LiP-MS and Molecular Dynamics Simulations Applied to KRas G12D Inhibitors.Analytical chemistry · 2025Article
- Site-directed antibodies targeting driver mutations of the KRAS protein.New biotechnology · 2025Article
- Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.ChemMedChem · 2025Article
- Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Recent Anti-KRASCancers · 2025Review
- Inhibition and degradation of NRAS with a pan-NRAS monobody.Oncogene · 2024Article
- Cytosolic delivery of monobodies using the bacterial type III secretion system inhibits oncogenic BCR: ABL1 signaling.Cell communication and signaling : CCS · 2024Article
- Current and future immunotherapeutic approaches in pancreatic cancer treatment.Journal of hematology & oncology · 2024Review
- Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells.The Journal of biological chemistry · 2024Article
- In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Article
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
The G12D mutation is among the most common KRAS mutations associated with cancer, in particular, pancreatic cancer. Here, we have developed monobodies, small synthetic binding proteins, that are selective to KRAS(G12D) over KRAS(wild type) and other oncogenic KRAS mutations, as well as over the G12D mutation in HRAS and NRAS. Crystallographic studies revealed that, similar to other KRAS mutant-selective inhibitors, the initial monobody bound to the S-II pocket, the groove between switch II and α3 helix, and captured this pocket in the most widely open form reported to date. Unlike other G12D-selective polypeptides reported to date, the monobody used its backbone NH group to directly recognize the side chain of KRAS Asp12, a feature that closely resembles that of a small-molecule inhibitor, MTRX1133. The monobody also directly interacted with H95, a residue not conserved in RAS isoforms. These features rationalize the high selectivity toward the G12D mutant and the KRAS isoform. Structure-guided affinity maturation resulted in monobodies with low nM
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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.