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Rapid Identification of Novel Allosteric PRC2 Inhibitors
journal contribution
posted on 2019-09-23, 16:33 authored by Jon A. Read, Jonathan Tart, Philip B. Rawlins, Clare Gregson, Karen Jones, Ning Gao, Xiahui Zhu, Ron Tomlinson, Erin Code, Tony Cheung, Huawei Chen, Sameer P. Kawatkar, Andy Bloecher, Sharan Bagal, Daniel H. O’Donovan, James RobinsonEnhancer 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.
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Novel Allosteric PRC 2 Inhibitors EnhancerEZH 2 activityPRC 2 core subunitPRC 2 methyltransferase activityhigh-throughput screeningzeste homologue 2fluorescence polarization probemethylating histone H 3 lysine 27. EZH 2EED binding compoundsgene expressionhematological malignanciesHTSchromatin stateorthosteric EZH 2 inhibitiondeconvolution challengeRapid Identificationnovel allosteric PRC 2 inhibitorscell lines