Natural Product-Inspired Molecules for Covalent Inhibition of SHP2 Tyrosine Phosphatase

Tetrahedron. 2024 Apr 28;156:133918. doi: 10.1016/j.tet.2024.133918. Epub 2024 Mar 2.ABSTRACTNatural 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 ent-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 ent-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.PMID:38618612 | PMC:PMC11008911 | DOI:10.1016/j.tet.2024.133918
Source: Tetrahedron - Category: Chemistry Authors: Source Type: research