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Rapid identification of novel allosteric PRC2 inhibitors

DOI: 10.1021/acschembio.9b00468 DOI Help

Authors: Jon A. Read (AstraZeneca) , Jonathan Tart (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Clare Gregson (AstraZeneca) , Karen Jones (AstraZeneca) , Ning Gao (AstraZeneca) , Xiahui Zhu (AstraZeneca) , Ron Tomlinson (AstraZeneca) , Erin Code (AstraZeneca) , Tony Cheung (AstraZeneca) , Huawei Chen (AstraZeneca) , Sameer P. Kawatkar (AstraZeneca) , Andy Bloecher (AstraZeneca) , Sharan Bagal (AstraZeneca) , Daniel H. O’donovan (AstraZeneca) , James Robinson (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: September 2019

Abstract: Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates chromatin state and gene expression by methylating histone H3 lysine 27. EZH2 is overexpressed or mutated in various hematological malignancies and solid cancers. Our previous efforts to identify inhibitors of PRC2 methyltransferase activity by high-throughput screening (HTS) resulted in large numbers of false positives and thus a significant hit deconvolution challenge. More recently, others have reported compounds that bind to another PRC2 core subunit, EED, and allosterically inhibit EZH2 activity. This mechanism is particularly appealing as it appears to retain potency in cell lines that have acquired resistance to orthosteric EZH2 inhibition. By designing a fluorescence polarization probe based on the reported EED binding compounds, we were able to quickly and cleanly re-triage our previously challenging HTS hit list and identify novel allosteric PRC2 inhibitors.

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


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