Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold

In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor. Employing a promising but nonselective CDK11-targeting scaffold (JWD-047), extensive structure-guided medicinal chemistry modifications led to the identification of ZNL-05-044. A combination of biochemical evaluations and NanoBRET cellular assays for target engagement guided the SAR towards a 2,4-diaminothiazoles CDK11 probe with significantly improved kinome-wide selectivity over JWD-047. CDK11 inhibition with ZNL-05-044 leads to G2/M cell cycle arrest, consistent with prior work evaluating OTS964, and impacts CDK11-dependent mRNA splicing in cells. Together, ZNL-05-044 serves as a tool compound for further optimization and interrogation of the consequences of CDK11 inhibition.PMID:35597007 | DOI:10.1016/j.ejmech.2022.114433

Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Zhengnian Li Ryosuke Ishida Yan Liu Jinhua Wang Yina Li Yang Gao Jie Jiang Jianwei Che Jason M Sheltzer Matthew B Robers Tinghu Zhang Kenneth D Westover Behnam Nabet Nathanael S Gray Source Type: research