Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β‑Glucocerebrosidase

β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher’s disease and are a major genetic risk factor for Parkinson’s disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and incr...

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Published in:Journal of medicinal chemistry 2024-07, Vol.67 (13), p.11168-11181
Main Authors: Palmer, Nick, Agnew, Christopher, Benn, Caroline, Buffham, William J., Castro, Joan N., Chessari, Gianni, Clark, Mellissa, Cons, Benjamin D., Coyle, Joseph E., Dawson, Lee A., Hamlett, Christopher C. F., Hodson, Charlotte, Holding, Finn, Johnson, Christopher N., Liebeschuetz, John W., Mahajan, Pravin, McCarthy, James M., Murray, Christopher W., O’Reilly, Marc, Peakman, Torren, Price, Amanda, Rapti, Magdalini, Reeks, Judith, Schöpf, Patrick, St-Denis, Jeffrey D., Valenzano, Chiara, Wallis, Nicola G., Walser, Reto, Weir, Heather, Wilsher, Nicola E., Woodhead, Andrew, Bento, Carla F., Tisi, Dominic
Format: Article
Language:English
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Summary:β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher’s disease and are a major genetic risk factor for Parkinson’s disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase. The fragment hits were identified by using X-ray crystallography and biophysical techniques. This work led to the discovery of a series of compounds that bind GCase with nM potency and positively modulate GCase activity in cells.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00702