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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)