2. Academic Validation
  3. Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase

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

  • J Med Chem. 2024 Jul 11;67(13):11168-11181. doi: 10.1021/acs.jmedchem.4c00702.
Nick Palmer 1,  Christopher Agnew 1,  Caroline Benn 1,  William J Buffham 1,  Joan N Castro 1,  Gianni Chessari 1,  Mellissa Clark 1,  Benjamin D Cons 1,  Joseph E Coyle 1,  Lee A Dawson 1,  Christopher C F Hamlett 1,  Charlotte Hodson 1,  Finn Holding 1,  Christopher N Johnson 1,  John W Liebeschuetz 1,  Pravin Mahajan 1,  James M McCarthy 1,  Christopher W Murray 1,  Marc O'Reilly 1,  Torren Peakman 1,  Amanda Price 1,  Magdalini Rapti 1,  Judith Reeks 1,  Patrick Schöpf 1,  Jeffrey D St-Denis 1,  Chiara Valenzano 1,  Nicola G Wallis 1,  Reto Walser 1,  Heather Weir 1,  Nicola E Wilsher 1,  Andrew Woodhead 1,  Carla F Bento 1,  Dominic Tisi 1
Affiliations

Affiliation

  • 1 Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
PMID: 38932616 DOI: 10.1021/acs.jmedchem.4c00702
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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