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Ref Type Journal Article
PMID (37339170)
Authors Keats M, Han JJW, Lee YH, Lee CS, Luo J
Title A non-conserved histidine residue on KRAS drives paralog selectivity of the KRASG12D inhibitor MRTX1133.
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Abstract Text MRTX1133 is the first non-covalent inhibitor against the KRASG12D mutant that demonstrated specificity and potency in pre-clinical 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 wildtype KRAS protein. In contrast, MRTX1133 exhibited no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards 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 towards MRTX1133. Thus, H95 is an essential selectivity handle for MRTX1133 towards KRAS. Amino acid diversity at residue 95 could facilitate the discovery of pan-KRAS inhibitors as well as HRAS and NRAS paralog-selective inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
HRAS Q95H missense unknown HRAS Q95H does not lie within any known functional domains of the Hras protein (UniProt.org). Q95H has been identified in the scientific literature (PMID: 37339170), but has not been biochemically characterized and therefore, its effect on Hras protein function is unknown (PubMed, Jan 2024)
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS G12D HRAS Q95H Advanced Solid Tumor sensitive MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing HRAS G12D and HRAS Q95H were sensitive to treatment with MRTX1133, demonstrating decreased cell viability (PMID: 37339170). 37339170
HRAS G12D Advanced Solid Tumor no benefit MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing HRAS G12D were not sensitive to treatment with MRTX1133 (PMID: 37339170). 37339170
NRAS G12D NRAS L95H Advanced Solid Tumor sensitive MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing NRAS G12D and NRAS L95H were sensitive to treatment with MRTX1133, demonstrating decreased cell viability (PMID: 37339170). 37339170
NRAS G12D multiple myeloma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring NRAS G12D was sensitive to treatment with Mekinist (trametinib) in culture, demonstrating decreased cell viability (PMID: 37339170). 37339170
NRAS G12D Advanced Solid Tumor no benefit MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing NRAS G12D were not sensitive to treatment with MRTX1133 (PMID: 37339170). 37339170
NRAS G12D multiple myeloma no benefit MRTX-1133 Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring NRAS G12D was not sensitive to treatment with MRTX1133 in culture (PMID: 37339170). 37339170