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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
41 Downloads (Pure)

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.

Original languageEnglish
Article number781213
Pages (from-to)1-11
Number of pages11
JournalFrontiers in Chemistry
Volume9
DOIs
Publication statusPublished - 13 Dec 2021

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • actin cytoskeleton
  • cofilin phosphorylation
  • kinase inhibitor
  • LIMK
  • SAR

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