J Chem Inf Model - Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.

Tópicos

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Resumo

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.

Resumo Limpo

protein kinas ck ck ubiquit serinethreonin protein kinas hundr endogen substrat serv attract anticanc target one potent inhibitor cx enter phase clinic trial herein present integr workflow combin shapebas virtual screen identif novel ck inhibitor shapebas model deriv cx built subsequ virtual screen led identif sever novel scaffold high shape similar cx among two tricycl scaffold name triazolocquinazolin triazoloaquinoxalin attract us combin strict chemic similar analysi secondround shapebas screen perform base two tricycl scaffold lead deriv compound target ck potent dosedepend activ also show accept antiprolif effect seri cancer cell line workflow suppli high effici strategi identif novel ck inhibitor compound report can serv ideal lead modif

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