Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase

DOI: 10.1016/j.bmcl.2021.127904

Authors: Daniel H. O' Donovan (AstraZeneca) , Clare Gregson (AstraZeneca) , Martin J. Packer (AstraZeneca) , Ryan Greenwood (AstraZeneca) , Kurt G. Pike (AstraZeneca) , Sameer Kawatkar (AstraZeneca) , Andrew Bloecher (AstraZeneca) , James Robinson (AstraZeneca) , Jon Read (AstraZeneca) , Erin Code (Discovery Sciences R&D) , Jessie Hao-Ru Hsu (AstraZeneca) , Minhui Shen (AstraZeneca) , Haley Woods (AstraZeneca) , Peter Barton (AstraZeneca) , Shaun Fillery (AstraZeneca) , Beth Williamson (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Sharan K. Bagal (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 39

State: Published (Approved)
Published: May 2021

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.

Journal Keywords: Free Energy Perturbation; Late stage functionalisation; PRC2; EED; EZH2

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 19/07/2021 10:46

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)