Format

Send to

Choose Destination
Sci Rep. 2019 Apr 25;9(1):6524. doi: 10.1038/s41598-019-43005-z.

Discovery of selective activators of PRC2 mutant EED-I363M.

Author information

1
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
2
Foghorn Therapeutics, Cambridge, MA, 02142, USA.
3
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
4
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada. Cheryl.Arrowsmith@uhnresearch.ca.
5
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. Cheryl.Arrowsmith@uhnresearch.ca.
6
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA. svfrye@email.unc.edu.

Abstract

Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. Polycomb repressive complex 2 (PRC2), which contains core subunits (EZH2, EED, and SUZ12), regulates gene activity by trimethylation of histone 3 lysine 27. The dysregulation of PRC2 catalytic activity by mutations has been implicated in cancer and other diseases. Among the mutations that cause PRC2 malfunction, an I363M LOF mutation of EED has been identified in myeloid disorders, where it prevents allosteric activation of EZH2 catalysis. We describe structure-based design and computational simulations of ligands created to ameliorate this LOF. Notably, these compounds selectively stimulate the catalytic activity of PRC2-EED-I363M over wildtype-PRC2. Overall, this work demonstrates the feasibility of developing targeted therapeutics for PRC2-EED-I363M that act as allosteric agonists, potentially correcting this LOF mutant phenotype.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center