Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Cancer Res. 2023 Sep 1;83(17):2816-2823. doi: 10.1158/0008-5472.CAN-23-0592.
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.
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.
MRTX1133 是首个针对 KRASG12D 突变体的非共价抑制剂，在临床前肿瘤模型中表现出特异性和效力。在这里，我们使用表达单一 RAS 等位基因的同基因细胞系来评估该化合物的选择性。除了 KRASG12D，MRTX1133 还对其他几种 KRAS 突变体以及野生型 KRAS 蛋白表现出显著的活性。相比之下，MRTX1133 对 HRAS 和 NRAS 蛋白的 G12D 和野生型形式均无活性。功能分析表明，MRTX1133 对 KRAS 的选择性与其与 KRAS 上的 H95 结合有关，HRAS 和 NRAS 中没有保守的 H95 残基。三个 RAS 同源物之间的 95 号氨基酸的相互突变导致它们对 MRTX1133 的敏感性发生相互变化。因此，H95 是 MRTX1133 对 KRAS 的必需选择性处理。95 号残基的氨基酸多样性可以促进 pan-KRAS 抑制剂以及 HRAS 和 NRAS 同源物选择性抑制剂的发现。
KRAS 上的非保守 H95 残基是 KRASG12D 抑制剂 MRTX1133 选择性所必需的，可用于开发 pan-KRAS 抑制剂。
