Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cell Chem Biol. 2017 Aug 17;24(8):1005-1016.e3. doi: 10.1016/j.chembiol.2017.06.017. Epub 2017 Aug 3.
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.
针对 KRAS G12C 驱动的癌症，靶向共价小分子显示出巨大的潜力。已经报道了能够进入由 KRAS 中动态结构元件移动形成的诱导口袋的别构化合物，但这些化合物需要进一步优化，以使其能够进入临床开发。我们证明，基于共价喹唑啉的开关 II 口袋（SIIP）化合物能够有效地抑制 KRAS G12C 的 GTP 加载、MAPK 磷酸化以及携带 G12C 的癌细胞的生长。值得注意的是，我们发现向喹唑啉支架中添加酰胺取代基可以与 KRAS G12C 进行额外的相互作用，并显著提高 KRAS G12C 抑制剂的标记效率、效力和选择性。使用 X 射线晶体学的结构研究揭示了 SIIP 的新构象以及位于喹唑啉 2-、4-和 7-位的取代基所形成的关键相互作用。优化后的喹唑啉系列中的先导化合物以亚微摩尔浓度选择性地抑制 KRAS G12C 依赖性信号传导和癌细胞生长。
