Natural products have been playing indispensable roles in the development of lifesaving drug molecules. They are also valuable sources for covalent protein modifiers. However, they often are scarce in nature and have complex chemical structures, which are limiting their further biomedical development. Thus, natural product-inspired small molecules which still contain the essence of the parent natural products but are readily available and amenable for structural modification, are important and desirable in searching for lead compounds for various disease treatment. Inspired by the complex and diverse -kaurene diterpenoids with significant biological activities, we have created a synthetically accessible and focused covalent library by incorporating the bicyclo[3.2.1]octane α-methylene ketone, which is considered as the pharmacophore of -kaurene diterpenoids, as half of the structure, and replacing the other half with much less complex but more druglike scaffolds. From this library, we have identified and characterized selective covalent inhibitors of protein tyrosine phosphatase SHP2, an important anti-cancer therapeutic target. The success of this study demonstrated the importance of creating and evaluating natural product-inspired library as well as their application in targeting challenging disease targets.

中文翻译：

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用于共价抑制 SHP2 酪氨酸磷酸酶的天然产物分子

天然产物在救生药物分子的开发中发挥着不可或缺的作用。它们也是共价蛋白修饰剂的宝贵来源。然而，它们在自然界中往往稀缺且具有复杂的化学结构，这限制了它们的进一步生物医学发展。因此，受天然产物启发的小分子仍然含有母体天然产物的本质，但易于获得并易于进行结构修饰，在寻找用于各种疾病治疗的先导化合物中是重要且理想的。受复杂多样且具有显着生物活性的贝壳杉烯二萜类化合物的启发，我们通过结合双环[3.2.1]辛烷α-亚甲基酮（被认为是贝壳杉烯二萜类化合物的药效基团）创建了一个可合成的、可合成的、集中的共价库，作为结构的一半，并用不太复杂但更类似于药物的支架取代另一半。从这个库中，我们鉴定并表征了蛋白酪氨酸磷酸酶 SHP2（一个重要的抗癌治疗靶点）的选择性共价抑制剂。这项研究的成功证明了创建和评估天然产物库及其在针对具有挑战性的疾病目标中的应用的重要性。