LIM结构域激酶(LIMK)家族由两个亚型组成,LIMK1和LIMK2高度同源,使选择性抑制剂的开发具有挑战性。LIMK调节肌动蛋白细胞骨架的动力学,从而影响许多细胞功能,包括细胞形态和运动性。这里,我们设计并合成了一种已知的吡咯并嘧啶LIMK抑制剂的类似物,该抑制剂对LIMK1的选择性相对于LIMK2中等,以了解哪些特征对活性和选择性都有贡献.我们在环己基中心部分周围引入了不同的立体化学,以实现对不同LIMK亚型的更好选择性。抑制活性通过激酶测定进行评估,并使用体外伤口闭合试验确定细胞中的生物学效应。有趣的是,立体化学的轻微变化改变了LIMK同工型选择性。最后,进行了一项对接研究,以预测新化合物如何与靶标相互作用.
The LIM-domain kinase (LIMK) family consists of two isoforms, LIMK1 and LIMK2, which are highly homologous, making selective inhibitor development challenging. LIMK regulates dynamics of the actin cytoskeleton, thereby impacting many cellular functions including cell morphology and motility. Here, we designed and synthesised analogues of a known pyrrolopyrimidine LIMK inhibitor with moderate selectivity for LIMK1 over LIMK2 to gain insights into which features contribute to both activity and selectivity. We incorporated a different stereochemistry around a cyclohexyl central moiety to achieve better selectivity for different LIMK isoforms. Inhibitory activity was assessed by kinase assays, and biological effects in cells were determined using an in vitro wound closure assay. Interestingly, a slight change in stereochemistry alters LIMK isoform selectivity. Finally, a docking study was performed to predict how the new compounds interact with the target.