Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase PMID: 38932616

ADC Targets in Oncology

2026-04-10

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

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.