化学
环肽
生物活性
化学合成
组合化学
立体化学
生物化学
体外
肽
作者
József Petró,Gyula Bényei,Péter Bana,Nikolett Linke,Ferenc Horti,J. Szabó,Krisztina Szalai,Gábor Hornyánszky,István Greiner,János Éles
标识
DOI:10.1016/j.bmcl.2024.129643
摘要
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.
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