9FB2

Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of beta-Glucocerebrosidase.

Palmer, N., Agnew, C., Benn, C., Buffham, W.J., Castro, J.N., Chessari, G., Clark, M., Cons, B.D., Coyle, J.E., Dawson, L.A., Hamlett, C.C.F., Hodson, C., Holding, F., Johnson, C.N., Liebeschuetz, J.W., Mahajan, P., McCarthy, J.M., Murray, C.W., O'Reilly, M., Peakman, T., Price, A., Rapti, M., Reeks, J., Schopf, P., St-Denis, J.D., Valenzano, C., Wallis, N.G., Walser, R., Weir, H., Wilsher, N.E., Woodhead, A., Bento, C.F., Tisi, D.

(2024) J Med Chem 67: 11168-11181

• PubMed: 38932616 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.4c00702
• Primary Citation of Related Structures:  
  9F9Z, 9FA3, 9FA6, 9FAD, 9FAL, 9FAY, 9FAZ, 9FB2, 9FDI


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.