Hit expansion of allosteric GALK1 inhibitors for galactosemia

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Classic galactosemia is a rare disorder of galactose metabolism, with very disappointing outcomes, representing a heavy burden on the patients' quality of life and on the healthcare systems. Its current standard of care, a galactose-restricted diet, fails to prevent cognitive, neurological, social and fertility impairments. This proposal aims to advance the frontiers of galactosemia successful treatment, using a small molecule-based approach.Our approach aims to address the root cause of disease, which is the toxic accumulation of galactose-1-phosphate, through inhibiting the GALK1-catalysed biosynthesis of this metabolite. GALK1 (galactokinase 1) is a valued, validated therapeutic target, with demonstrated proof of concept in cell-based and animal disease models.Our proposal applies structural based approaches towards hit optimisation of GALK1 inhibitors, combining expertise and track record in computational chemistry (Daniel Cole), medicinal chemistry (Celine Cano) and structural biology (Wyatt Yue) at Newcastle University.Prior to this proposal, our project team has:established GALK1 protein production, activity and binding assays, and co-crystal structure determination in place for a drug discovery programme;identified and verified three compound series able to inhibit GALK1 via an allosteric binding mode;applied computational de novo design, docking and molecular dynamics to optimise ligand design towards targeting GALK1; andprogressed, using fewer than 60 follow-up compounds, from inactive fragments to three promising inhibitory series, enabled by computational and medicinal chemistry, and enriched through a wealth of co-structures.Through 3 work packages, our project team will apply computational and medicinal chemistry approaches to the design and generation of new compounds based on our chemical starting points, and characterise the binding, potency, and selectivity of these compounds in biophysical and structural assays. Based on the assay profiles we will identify one series for focused efforts to fine-tune compounds through design-synthesis-assay cycles. Finally, we will determine the ability of our best compounds to target GALK1 and generate functional impact in human cells.Through this proposal we set out to de-risk early-stage drug discovery for a rare disease, to advance our chemical starting points into validated hits, and to deliver a promising compound paving the route for lead development.There is a clear downstream pathway for development:Through engagement with US-based Galactosemia Foundation and the EU-based Galactosemia Network, the project lead has networked and collaborated with clinical and research leaders in the field (Bosch, Amsterdam; Gozalbo-Rubio, Maastricht; Riviera, Lisbon; Treacy, Dublin; Lai, Utah). These collaborators will be key to characterising our lead inhibitors arising from this proposal in their cell-based (patient-derived fibroblast and iPSC lines) and organism (zebrafish, mouse) models of disease for in vitro and in vivo efficacy through metabolic flux, enzyme activity and phenotypic analyses. Additionally, we have identified and engaged in discussion with biotech/pharma partners with potential interest in the GALK1 inhibitor programme. Working together, our vision is a first-in-class small molecule inhibitor to treat classic galactosemia.