ArticleCancer research2023
A Nonconserved Histidine Residue on KRAS Drives Paralog Selectivity of the KRASG12D Inhibitor MRTX1133.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 18 citations in OpenAlex.
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- Benchmarking docking and ML re-scoring screening performance for KRAS G12D in pancreatic cancer.Molecular diversity · 2026Article
- Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Efficacy of dual KRASCell death & disease · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- Dual Inhibitors of KRASG12D and HSP90 Are Effective against KRASG12D Inhibitor Resistance.Molecular cancer therapeutics · 2026Article
- Emerging KRAS G12D inhibitor in the treatment of digestive system tumors: opportunities and challenges.Translational gastroenterology and hepatology · 2026Review
- Novel paradigms in KRAS targeting: Unveiling strategies to combat drug resistance.Chinese medical journal · 2025Review
- Enhancing KRAS G12D inhibitor sensitivity in pancreatic cancer through SHP2/PI3K pathway.Medical oncology (Northwood, London, England) · 2025Article
- A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers.BJC reports · 2025Article
- Article
- KRAS inhibitors: resistance drivers and combinatorial strategies.Trends in cancer · 2025Review
- Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.Nature chemical biology · 2024Article
- A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Targeting KRAS in pancreatic cancer.Oncology research · 2024Review
- Antitumor effect of a small-molecule inhibitor of KRASExperimental hematology & oncology · 2023Article
- Ability ofCancers · 2023Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
MRTX1133 is the first noncovalent inhibitor against the KRASG12D mutant that demonstrated specificity and potency in preclinical tumor models. Here, we used isogenic cell lines expressing a single RAS allele to evaluate the selectivity of this compound. In addition to KRASG12D, MRTX1133 showed significant activity against several other KRAS mutants as well as wild-type KRAS protein. In contrast, MRTX1133 exhibited no activity against both G12D and wild-type forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 toward KRAS is associated with its binding to H95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three RAS paralogs resulted in reciprocal change in their sensitivity toward MRTX1133. Thus, H95 is an essential selectivity handle for MRTX1133 toward KRAS. Amino acid diversity at residue 95 could facilitate the discovery of pan-KRAS inhibitors as well as HRAS and NRAS paralog-selective inhibitors. SIGNIFICANCE: The nonconserved H95 residue on KRAS is required for the selectivity of the KRASG12D inhibitor MRTX1133 and can be exploited for the development of pan-KRAS inhibitors.
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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.