ArticleCell discovery2022
KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge.
Article in Cell discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
83 citing papers in PubMed, 138 citations in OpenAlex.
- KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRASNature medicine · 2026Trial
- Safety and efficacy of lapatinib, binimetinib, and vinorelbine for RAS mutant metastatic colorectal cancer: results of the RASTRIC Phase I/II trial.British journal of cancer · 2026Trial
- Design, synthesis and biological evaluation of novel KRAS-G12D inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- A ternary association of KRas, EphA2, and integrins controls PDAC cell behavior.The Journal of biological chemistry · 2026Article
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- Benchmarking docking and ML re-scoring screening performance for KRAS G12D in pancreatic cancer.Molecular diversity · 2026Article
- Piperazine derivatives as anticancer agents: a medicinal chemistry review of structure, mechanism, and clinical translation.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- A Molecular-Protein Fusion Framework for Rapid Virtual Screening: Accelerating Lead Discovery for "Undruggable'' Oncogenic Targets.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRASG12D Inhibitor.Cancer discovery · 2026Article
- Computational insights on the molecular interplay between KRas (G12D mutation) and SOS1 modulated by the inhibitor BI-3406.PLoS computational biology · 2026Article
- Article
- HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis.The Journal of clinical investigation · 2026Article
- Antimetastatic effects of MRTX1133 KRAS G12D specific inhibitor in a liver metastatic model of pancreatic ductal adenocarcinoma.Scientific reports · 2026Article
- Stability-Driven Pose Prediction and Ligand Design via Contact Persistence Analysis from Molecular Dynamics Simulations.Computational and structural biotechnology journal · 2026Article
- Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma.bioRxiv : the preprint server for biology · 2025Article
- Multi-omics analysis reveals cell adhesion molecules as key regulators of immune cell infiltration and adverse outcomes and in vitro validation of CLDN16 in pancreatic adenocarcinoma.Cellular and molecular life sciences : CMLS · 2025Article
- Targeting KRAS G12D: Advances in Inhibitor Design.Thoracic cancer · 2025Review
- Quantum-computing-enhanced algorithm unveils potential KRAS inhibitors.Nature biotechnology · 2025Article
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- Driving Precision Medicine in Pancreatic Cancer With Molecular Genetics.Seminars in radiation oncology · 2025Review
23 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS(G12D) variant still lacks inhibitors. Herein, we designed a series of potent inhibitors that can form a salt bridge with KRAS's Asp12 residue. Our ITC results show that these inhibitors have similar binding affinity with both GDP-bound and GTP-bound KRAS(G12D), and our crystallographic studies reveal the structural basis of inhibitor binding-induced switch-II pocket in KRAS(G12D), experimentally confirming the formation of a salt bridge between the piperazine moiety of the inhibitors and the Asp12 residue of the mutant protein. Among KRAS family proteins and mutants, both ITC and enzymatic assays demonstrate the selectivity of the inhibitors for KRAS(G12D); and the inhibitors disrupt the KRAS-CRAF interaction. We also observed the inhibition of cancer cell proliferation as well as MAPK signaling by a representative inhibitor (TH-Z835). However, since the inhibition was not fully dependent on KRAS mutation status, it is possible that our inhibitors may have off-target effects via targeting non-KRAS small GTPases. Experiments with mouse xenograft models of pancreatic cancer showed that TH-Z835 significantly reduced tumor volume and synergized with an anti-PD-1 antibody. Collectively, our study demonstrates proof-of-concept for a strategy based on salt-bridge and induced-fit pocket formation for KRAS(G12D) targeting, which warrants future medicinal chemistry efforts for optimal efficacy and minimized off-target effects.
Identifiers
What OpenQuestion holds
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.