Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

中文翻译：

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KRAS G12C的强效和选择性共价喹唑啉抑制剂

靶向共价小分子已显示出对由KRAS G12C引发的癌症的希望。已经报道了通过KRAS动态结构元件的运动（开关II）接近可诱导口袋的变构化合物，但是这些化合物需要进一步优化以使其进入临床开发。我们证明基于共价喹唑啉的开关II口袋（SIIP）化合物可有效抑制KRAS G12C的GTP负载，MAPK磷酸化和包含G12C的癌细胞的生长。值得注意的是，我们发现将酰胺基取代基添加到喹唑啉支架上可以与KRAS G12C进行其他相互作用，并显着提高KRAS G12C抑制剂的标记效率，效价和选择性。使用X射线晶体学的结构研究揭示了SIIP的新构型以及由位于喹唑啉2、4和7位的取代基形成的关键相互作用。在亚微摩尔浓度下，喹唑啉系列中优化的先导化合物选择性抑制KRAS G12C依赖性信号传导和癌细胞生长。