School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, PR China.
Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.
Bioorg Chem. 2023 Jul;136:106536. doi: 10.1016/j.bioorg.2023.106536. Epub 2023 Apr 10.
KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many deadliest cancers. Son of sevenless homolog 1 (SOS1) is a crucial regulator of KRAS to modulate KRAS from inactive to active states. We previously discovered tetra-cyclic quinazolines as an improved scaffold for inhibiting SOS1-KRAS interaction. In this work, we report the design of tetra-cyclic phthalazine derivatives for selectively inhibiting SOS1 against EGFR. The lead compound 6c displayed remarkable activity to inhibit the proliferation of KRAS(G12C)-mutant pancreas cells. 6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.
KRAS 突变（G12C、G12D 等）与许多最致命癌症的发生和发展有关。七次跨膜蛋白 1（SOS1）是 KRAS 的关键调节因子，可调节 KRAS 从非活性状态转变为活性状态。我们之前发现四环喹唑啉类化合物是一种改进的抑制 SOS1-KRAS 相互作用的支架。在这项工作中，我们设计了四环邻苯二甲嗪衍生物，用于选择性抑制 SOS1 对 EGFR 的作用。先导化合物 6c 对抑制 KRAS(G12C)突变胰腺细胞的增殖显示出显著的活性。6c 在体内表现出良好的药代动力学特性，生物利用度为 65.8%，并在胰腺肿瘤异种移植模型中表现出强烈的肿瘤抑制作用。这些有趣的结果表明，6c 有可能被开发为 KRAS 驱动的肿瘤的候选药物。
