Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR,ACS Medicinal Chemistry Letters

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Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2024-04-05 , DOI: 10.1021/acsmedchemlett.3c00425
Nils Pemberton ₁ , Nina Compagne ₁ , Argyrides Argyrou ₂ , Emma Evertsson ₁ , Anders Gunnarsson ₃ , Jason G Kettle ₄ , Jonathan P Orme ₂ , Richard A Ward ₄

Affiliation

To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine 6 as a starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12, which shows high EGFR potency and good kinase selectivity, as well as significantly reduced reactivity compared to the starting compound 6, confirming that vinylpyridines can be applied as an alternative cysteine reactive warhead with tunable reactivity.

中文翻译：

乙烯基吡啶作为可调谐共价弹头，靶向 EGFR 中的 C797

为了进一步促进半胱氨酸反应性共价抑制剂的发现，需要开发传统丙烯酰胺型弹头之外的新反应基团。在此，我们描述了使用乙烯基吡啶作为反应基团的共价 EGFR 抑制剂的设计和合成。基于结构的设计确定了含有喹唑啉的乙烯基吡啶6作为起点。进一步的修饰集中在降低反应性上，产生了取代的乙烯基化合物12 ，它表现出高EGFR效力和良好的激酶选择性，并且与起始化合物6相比反应性显着降低，证实乙烯基吡啶可以用作替代的半胱氨酸反应性弹头，具有可调性。反应性。

更新日期：2024-04-05

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