TY - JOUR
T1 - Small-molecule modulators of methyl-lysine binding for the CBX7 chromodomain
AU - Ren, Chunyan
AU - Morohashi, Keita
AU - Plotnikov, Alexander N.
AU - Jakoncic, Jean
AU - Smith, Steven G.
AU - Li, Jiaojie
AU - Zeng, Lei
AU - Rodriguez, Yoel
AU - Stojanoff, Vivian
AU - Walsh, Martin
AU - Zhou, Ming Ming
N1 - Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/2/19
Y1 - 2015/2/19
N2 - 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 trimethylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report the 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, derepresses 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.
AB - 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 trimethylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report the 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, derepresses 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.
UR - http://www.scopus.com/inward/record.url?scp=84923196669&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2014.11.021
DO - 10.1016/j.chembiol.2014.11.021
M3 - Article
C2 - 25660273
AN - SCOPUS:84923196669
SN - 1074-5521
VL - 22
SP - 161
EP - 168
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 2
ER -