Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

Abstract

SUMMARY Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, de-represses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.

Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

“…Our study has revealed a novel mechanism of Notch epigenetic regulation in breast cancer. In light of the recent development of compounds that inhibit Cbx function (Ren et al, 2015, Simhadri et al, 2014, Stuckey et al, 2016), our studies provide support for targeting Cbx8 as an alternative strategy to attenuate Notch signaling in breast cancer. Specificity of inhibitory compounds for Cbx orthologues will be essential for such therapeutic targeting.…”

Structure–Activity Relationships and Kinetic Studies of Peptidic Antagonists of CBX Chromodomains

“…Previous studies from the Zhou lab have reported weak, non-peptidic small molecule CBX7 ligands; however, SAR studies around these molecules struggled to produce significant improvements in potency. 21, 23 …”

Molecular Insights into Inhibition of the Methylated Histone-Plant Homeodomain Complexes by Calixarenes

“…Recent breakthroughs in biological and medical applications of small molecule antagonists for acetyllysine-binding bromodomain, methyllysine-binding MBT and chromodomain, and arginine-recognizing WD40 demonstrate the vast potential of targeting the histone readers (15)(16)(17)(18)(19)(20). A number of epigenetic inhibitors are in clinical trials as anticancer and antiinflammatory agents (15,21,22).…”