Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase. (1st May 2021)

• Record Type: Journal Article
• Authors: O' Donovan, Daniel H.; Gregson, Clare; Packer, Martin J.; Greenwood, Ryan; Pike, Kurt G.; Kawatkar, Sameer; Bloecher, Andrew; Robinson, James; Read, Jon; Code, Erin; Hsu, Jessie Hao-Ru; Shen, Minhui; Woods, Haley; Barton, Peter; Fillery, Shaun; Williamson, Beth; Rawlins, Philip B.; Bagal, Sharan K.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 39(2021)
• Publication Date: 2021-05-01
• Subjects: Free Energy Perturbation -- Late stage functionalisation -- PRC2 -- EED -- EZH2; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127904
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of triazolopyrimidine EED ligands is reported which explores a novel pocket within the binding site. Free Energy Perturbation (FEP) calculations were used to predict their affinity, as verified by surface plasmon resonance (SPR) A synthetic approach incorporating late-stage functionalization (LSF) enabled rapid exploration of SAR. New ligands retain high affinity for EED while improving their physicochemical properties. Abstract: Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.