Ariawan Daryl, Au Carol, Paric Esmeralda, Fath Thomas, Ke Yazi D, Kassiou Michael, van Eersel Janet, Ittner Lars M
Dementia Research Centre, Department of Biomedical Science, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
School of Chemistry, The University of Sydney, Darlington, NSW, Australia.
Front Chem. 2021 Dec 13;9:781213. doi: 10.3389/fchem.2021.781213. eCollection 2021.
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 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.
LIM结构域激酶（LIMK）家族由两种亚型LIMK1和LIMK2组成，它们高度同源，这使得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态变化，从而影响包括细胞形态和运动性在内的许多细胞功能。在此，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，该类似物对LIMK1的选择性高于LIMK2，以深入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引入了不同的立体化学结构，以实现对不同LIMK亚型更好的选择性。通过激酶测定评估抑制活性，并使用伤口闭合测定法确定细胞中的生物学效应。有趣的是，立体化学的轻微变化会改变LIMK亚型的选择性。最后，进行了对接研究以预测新化合物与靶点的相互作用方式。
