Authors

L Waters¹; R Collins¹; H Patel¹; J Atack²; 
¹ Medicines Discovery Institute, Cardiff University, UK;  ² Cardiff University, UK

Discussion

The LIM domain Kinase isoforms (LIMK1 and LIMK2) are dual-specificity kinases that regulate actin dynamics through the phosphorylation of actin depolymerising factor/ cofilin (ADF/CFL) protein family. CFL is a crucial downstream effector in the Rho/Rac/Cdc42 signalling pathways. The dysregulation in pathway activity result in altered actin-filament dynamics and has shown to drive several diverse pathological processes, ranging from cancers to the intellectual disability disorder fragile X syndrome (FXS) – characterised by an abnormal synaptic morphology. Pharmacological inhibition of LIMK1 in cellular and in vivo models have restored synaptic morphology and alleviated associated symptoms of FXS. In cancer biology, studies have shown LIMKs drive proliferation and metastatic phenotypes, particularly in acute myeloid leukaemia (AML) – a rare, but aggressive malignancy. Research has demonstrated LIMK1 inhibition reduced cell proliferation, colony formation and induced changes toward myeloid differentiation. Taken together, LIMKs represent critical targets for therapies across multiple indications of unmet need. Though common assays can be employed to determine biochemical activity, cellular target engagement and pathway impact for new compounds; to assess disease specific phenotypes, the development of highly bespoke assays are needed for the different indications. Herein, we describe the development of indication specific cellular assays to profile novel LIMK1 inhibitors and facilitate the optimisation of such inhibitors in the context of both FXS and AML.