The Nature of Diamino Linker and Halogen Bonding Define Selectivity of Pyrrolopyrimidine-Based LIMK1 Inhibitors

Daryl Ariawan; Carol Au; Esmeralda Paric; Thomas Fath; Yazi D Ke; Michael Kassiou; Janet van Eersel; Lars M Ittner

doi:10.3389/fchem.2021.781213

The Nature of Diamino Linker and Halogen Bonding Define Selectivity of Pyrrolopyrimidine-Based LIMK1 Inhibitors

Front Chem. 2021 Dec 13:9:781213. doi: 10.3389/fchem.2021.781213. eCollection 2021.

Authors

Daryl Ariawan¹, Carol Au¹, Esmeralda Paric¹, Thomas Fath¹, Yazi D Ke¹, Michael Kassiou², Janet van Eersel¹, Lars M Ittner¹

Affiliations

¹ Dementia Research Centre, Department of Biomedical Science, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
² School of Chemistry, The University of Sydney, Darlington, NSW, Australia.

Abstract

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.

Keywords: LIMK; SAR; actin cytoskeleton; cofilin phosphorylation; kinase inhibitor.