Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes.

SLAS discovery : advancing life sciences R & D 2022 Jul

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The dysregulation of the PRC1/2 complex plays a key role in lineage plasticity in prostate cancer and may be required to maintain neuroendocrine phenotype. [1] CBX2, a key component of the canonical PRC1 complex, is an epigenetic reader, recognizing trimethylated lysine on histone 3 (H3K27me3) [2] and is overexpressed in metastatic neuroendocrine prostate cancer. [3,4] We implemented a screening strategy using nucleosome substrates to identify inhibitors of CBX2 binding to chromatin. Construct design and phosphorylation state of CBX2 were critical for successful implementation and execution of an HTS library screen. A rigorous screening funnel including counter and selectivity assays allowed us to quickly focus on true positive hit matter. Two distinct non-peptide-like chemotypes were identified and confirmed in orthogonal biochemical and biophysical assays demonstrating disruption of CBX2 binding to nucleosomes and direct binding to purified CBX2, respectively. Copyright © 2022. Published by Elsevier Inc.

Citation

Lukas Lercher, Nina Simon, Andreas Bergmann, Marcel Tauchert, David Bochmann, Tarig Bashir, Torsten Neuefeind, Daniel Riley, Ben Danna, Paul Krawczuk, Vineet Pande, Aaron Patrick, Ruth Steele, Weixue Wang, Brent Rupnow, Peter Tummino, Sujata Sharma, Michael Finley. Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes. SLAS discovery : advancing life sciences R & D. 2022 Jul;27(5):306-313