Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC₅₀ value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5% inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.

中文翻译：

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含有三环喹唑啉支架的新型强效 SOS1 抑制剂：实验和模拟的联合视图


具有调节 Son of Sevenless 1 （SOS1） 和 Kristen 大鼠肉瘤 （KRAS） 之间相互作用能力的小分子在癌症治疗领域具有巨大的潜力。在这项研究中，我们提出了一系列具有三环喹唑啉支架的新型 SOS1 抑制剂。值得注意的是，我们已经鉴定出化合物 8d，它显示出最高的效力，IC₅₀ 值为 5.1 nM，用于破坏 KRAS：SOS1 相互作用。化合物 8d 表现出有前途的药代动力学特征，并在胰腺肿瘤异种移植模型中实现了显着的 70.5% 的肿瘤生长抑制。此外，分子动力学模拟揭示了三环喹唑啉衍生物与 Tyr884 的广泛相互作用，Tyr884 是识别 SOS1 和 KRAS 的关键残基。我们的研究结果为未来 SOS1 抑制剂的设计提供了新的见解，为创新的治疗策略铺平了道路。