Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research			2023 Jun 20		Cancer Res

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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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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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 2025)

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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
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	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
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 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

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