ArticleiScience2023
Global profiling of AMG510 modified proteins identified tumor suppressor KEAP1 as an off-target.
Article in iScience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- MXD4 enhances resistance to KRAS G12C-targeted therapy in lung adenocarcinoma by suppressing ACSL4-mediated ferroptosis.Respiratory research · 2026Article
- Engineered antibodies that stabilize drug-modified KRASNature communications · 2025Article
- Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs.British journal of cancer · 2025Article
- Panobinostat potentiates adagrasib-induced cell death by triggering autophagy in human non-small cell lung cancer.Cell death discovery · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- Inhibition of ULK1/2 and KRASeLife · 2024Article
- KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.Cell communication and signaling : CCS · 2024Article
- Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients WithJCO precision oncology · 2024Article
- A real-world pharmacovigilance study of KRAS G12C mutation inhibitors based on the food and drug administration adverse event reporting system.Frontiers in pharmacology · 2024Article
- K-RAS Is…Complicated.Cancers · 2023Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KRAS inhibitor AMG510 covalently modifies the G12C residue and inactivates the KRAS/G12C function. Because there are many reactive cysteines in the proteome, it is important to characterize AMG510 on-target modification and off-targets. Here, we presented a streamlined workflow to measure abundant AMG510 modified peptides including that of KRAS/G12C by direct profiling, and a pan-AMG510 antibody peptide IP workflow to profile less abundant AMG510 off-targets. We identified over 300 off-target sites with three distinct kinetic patterns, expanding the AMG510 modified proteome involved in the nucleocytoplasmic transport, response to oxidative stress, adaptive immune system, and glycolysis. We found that AMG510 covalently modified cys339 of ALDOA and inhibited its enzyme activity. Moreover, AMG510 modified KEAP1 cys288 and induced NRF2 accumulation in the nuclear of NSCLC cells independent of KRAS/G12C mutation. Our study provides a comprehensive resource of protein off-targets of AMG510 and elucidates potential toxicological sideeffects for this covalent KRASG12C inhibitor.
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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.