化学
连接器
细胞周期蛋白依赖激酶
泛素连接酶
激酶
泛素
蛋白质降解
小分子
生物化学
细胞周期
细胞
基因
计算机科学
操作系统
作者
Robert J. Tokarski,Chia M. Sharpe,Andrew C. Huntsman,Brittney K. Mize,Oluwatosin R. Ayinde,Emily Stahl,James R. Lerma,Andrew Reed,Bridget Carmichael,Natarajan Muthusamy,John C. Byrd,James R. Fuchs
标识
DOI:10.1016/j.ejmech.2023.115342
摘要
Cyclin-dependent kinase 9 (CDK9) is a promising therapeutic target in multiple cancer types, including acute myeloid leukemia (AML). Protein degraders, also known as proteolysis targeting chimeras (PROTACs), have emerged as tools for the selective degradation of cancer targets, including CDK9, complementing the activity of traditional small-molecule inhibitors. These compounds typically incorporate previously reported inhibitors and a known E3 ligase ligand to induce ubiquitination and subsequent degradation of the target protein. Although many protein degraders have been reported in the literature, the properties of the linker necessary for efficient degradation still require special attention. In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties.
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