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Executive summary

A novel Fat mass and obesity-associated protein (FTO) inhibitor with enhanced brain permeability and drug-like properties for the treatment of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s have been developed. Preliminary studies show neuroprotective effects in relevant models. The lead compound overcomes key limitations of previous candidates and is now progressing toward preclinical regulatory development.

Introduction

Neurodegenerative diseases are among the leading causes of disability and death worldwide, representing approximately 90% of all cases. Among them, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), represent challenging disorders, posing a major global health burden. Despite their distinct etiologies, none of the currently approved treatments have proven curative. Therefore, there is an urgent need to develop disease modifying treatments capable of alleviating symptoms, halting disease progression, and ultimately improving patients’ quality of life.
The multifactorial nature of these disorders and the lack of efficacy of previously tested mechanisms of action, highlight the potential of targeting epigenetic regulation as a promising pharmacological strategy for age-related neurodegenerative disorders.

Description

Evidence suggests that RNA m6A modifications play key roles in brain development, synaptic plasticity, neuronal signalling and pathogenesis of neurodegenerative diseases. M6A deficiency has been associated with synaptic loss, neuronal atrophy, and increased gliosis and resulting cognitive impairment and memory through several molecular pathways.
FTO, an m6A demethylase epigenetic enzyme highly expressed in brain, is responsible for erasing m6A and decreasing methylation levels. FTO has been linked to memory regulation, neurogenesis, and the pathology of both AD and HD through activation of the mTOR pathway. Consequently, several FTO inhibitors (FTOi) have been developed for cancer, most of them based from thon the well-known FTOi FB23, which does not cross the blood-brain barrier (BBB).
Recent findings indicate that epigenetic intervention hold considerable translational potential in neuroprotection, provided that key limitations are addressed (e.g. poor brain arrival, low selectivity and high toxicity). The lead FTOi, overcomes these limitations, offering a novel mechanism of action distinct from the marketed drugs.

Current stage of development

The group has performed a hit-to-lead optimization process, which has led to a family of compounds up to 7 times stronger and with better DMPK profile. An ongoing development plan is in place to validate the efficacy of the selected lead compound, which exhibits optimal drug-like properties, brain permeability and potent FTO inhibitory activity. The lead candidate has demonstrated good in vitro brain penetration and favorable DMPK profile. Preliminary in vivo studies in both AD and HD disease mouse models (SAMP8 and R6/1, respectively), as well as in vitro study for PD, have shown neuroprotective effects.
Therefore, the next steps will be to advance from research to preclinical regulatory development, including in vivo pharmacokinetics and efficacy assessments, dose optimization, and definition of the most suitable path to clinical and market translation.