LIMK1 inhibitors - A novel, disease-modifying approach for the treatment of fragile X syndrome

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences


Fragile X syndrome (FXS) is the most common inherited cause of learning disabilities and it affects around 1 in 5000 individuals (more common in males than females), and boys with FXS generally have more pronounced clinical symptoms than girls. It is characterised by learning difficulties, autism, behavioural challenges and social, emotional, attention and language problems as well as the potential to develop epilepsy. The clinical symptoms appear in early childhood and last into adulthood by which time the majority of FXS patients have also developed an anxiety disorder.
FXS is caused by a change in a single gene (the FMR1 gene) which alters production of a protein called FMRP. This protein is important in controlling the proper connection between nerve cells in the brain, allowing them to communicate effectively. This change in the FMR1 gene prevents production of the FMRP protein and leads to changes in the brain that result in the signs, behaviours and symptoms of FXS. Recent discoveries from several labs have uncovered key findings of the link between the loss of the FMRP protein and the changes that occur in the brain. Of particular interest has been the discovery of another protein, LIMK1, which acts as a master regulator and which is over-active in FXS individuals. Our approach is to design drug molecules which can inhibit this master regulator protein, and by doing so, reverse the impact of the loss of the FMRP protein. There are no currently approved drugs for FXS. Therefore, we believe this approach has a realistic chance to deliver a unique and transformative therapeutic agent for individuals with Fragile X.

Technical Summary

Fragile X syndrome (FXS) affects around 1 in 5000 individuals and is characterised by moderate to severe intellectual disability and autistic behaviours, as well as hypersensitivity to sensory stimuli and increased susceptibility to seizures; all as a consequence of abnormal synapse structure and function. There are no currently approved drugs for the treatment of FXS and there is therefore an urgent need for new therapeutic approaches. In FXS, an expansion of a CGG trinucleotide repeat in the FMR1 promoter results in loss of expression of fragile X mental retardation protein (FMRP) and a loss of FMRP-mediated transcriptional repression. However, only recently have two groups separately identified a causative association with synapse morphology, identifying signalling pathways involved in FMRP-associated synaptic dysfunction. Intriguingly, both these pathways converge on the relatively CNS-specific enzyme LIMK1 and proof of concept experiments have shown that inhibition of LIMK1 can rescue synapse structure and function in mouse and Drosophila models of FXS. Hence, LIMK1 represents an attractive new therapeutic approach to FXS. In this proposal we will use a medicinal chemistry strategy informed by iterative ligand-bound crystal structures to develop a recently identified LIMK1 inhibitor series and use exemplars to demonstrate both proof-of-principle in two models of FXS; dFmr1 mutant Drosophila motility assay and Fmr1 knockout mouse brain slice electrophysiology assay. The chemical series will then be ready for further optimisation to identify a clinical candidate with follow-on funding. Importantly, the LIMK1 inhibitor series identified is not a typical hinge-binding, ATP-competitive structure, but instead binds to a pocket near the ATP-binding site. This confers (1) exquisite selectivity, which will be essential to ensure the high tolerability required for a chronic therapy and (2) physicochemical properties predicted to be consistent with CNS-penetration.

Planned Impact

The primary goal of this research project is to take the first major step towards development of a therapeutic agent for patients with FXS. There are no drugs registered for FXS, and so this project represents a potential first opportunity for a targeted therapy for this disease.
Furthermore, the drugs developed could also have impact on other disease states such as autism and Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND).
The future development of this research project may have wider impact by attracting commercial investment and potentially lead to the formation of a spin out company, with associated job creation, to enable development.
Wider training of the scientists recruited onto this grant, in a fully supportive and enabled drug discovery environment, will provide a further cohort of skilled researchers who can contribute to the biotech/pharmaceutical research sector in future jobs.


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