Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: A joint view of experiments and simulations

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI:10.1016/j.ejmech.2024.117065

Luolong Qing , Zhengzai Cheng , Juan Xu , Ziwei Wang , Yuanyuan Li , Mario Gauthier , Silong Zhang , Huan He

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Abstract

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.

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含有三环喹唑啉支架的新型强效 SOS1 抑制剂：实验与模拟的共同视角

具有调节七无之子 1（SOS1）和克里斯汀大鼠肉瘤（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，我们提出了一系列新型 SOS1 抑制剂，它们具有三环喹唑啉支架。值得注意的是，我们发现了化合物 8d，它在破坏 KRAS:SOS1 相互作用方面表现出最高的效力，IC50 值为 5.1 nM。化合物 8d 具有良好的药代动力学特征，在胰腺肿瘤异种移植模型中对肿瘤生长的抑制率高达 70.5%。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 SOS1 与 KRAS 之间识别的关键残基。我们的发现为未来 SOS1 抑制剂的设计提供了新的见解，为创新治疗策略铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.