KRAS基因突变（G12C，G12D等）涉及许多最致命的癌症的癌变和进展。七个同源体儿子1（SOS1）是调节KRAS从非活动状态到活动状态的关键调节因子。我们先前发现四环喹唑啉作为抑制SOS1-KRAS相互作用的改进支架。在这项工作中，我们报告了四环噻嗪衍生物的设计，以选择性地抑制对EGFR的SOS1作用。引领化合物6c显示出抑制KRAS（G12C）突变胰腺细胞增殖的显着活性。6c在体内显示出有利的药代动力学特性，生物利用度为65.8％并在胰腺肿瘤移植模型中表现出强大的肿瘤抑制作用。这些有趣的结果表明6c具有成为KRAS驱动肿瘤候选药物的潜力。 Copyright©2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.