Structure–Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteins

dc.contributor.authorSimhadri, Chakravarthi
dc.contributor.authorGignac, Michael C.
dc.contributor.authorAnderson, Cameron J.
dc.contributor.authorMilosevich, Natalia
dc.contributor.authorDheri, Aman
dc.contributor.authorPrashar, Nishant
dc.contributor.authorFlemmer, Robert T.
dc.contributor.authorDev, Amarjot
dc.contributor.authorHenderson, Trevor G.
dc.contributor.authorDouglas, Sarah F.
dc.contributor.authorWulff, Jeremy E.
dc.contributor.authorHof, Fraser
dc.date.accessioned2020-06-18T23:24:21Z
dc.date.available2020-06-18T23:24:21Z
dc.date.copyright2016en_US
dc.date.issued2016
dc.description.abstracthe five human polycomb (Pc) paralog proteins, chromobox homolog (Cbx) 2/4/6/7/8, are a family of chromodomain containing methyllysine reader proteins that are canonical readers of trimethyllysine 27 on histone 3 (H3K27me3). The aberrant expression of the Cbx7 gene is implicated in several cancers including prostate, gastric, thyroid, pancreas, and colon cancer. Previous reports on antagonizing the molecular recognition of Cbx7–H3K27me3 with chemical inhibitors showed an impact on prostate cancer cell lines. We report here on the design, synthesis, and structure–activity relationships of a series of potent peptidomimetic antagonists that were optimized on a trimethyllysine-containing scaffold to target Cbx7. The ligands were characterized using fluorescence polarization (FP) for their binding efficiency and selectivity against the Pc paralog Cbx proteins. The most selective ligand 9, as indicated by the FP data analysis, was further characterized using the isothermal titration calorimetry (ITC). Compound 9 exhibits a 220 nM potency for Cbx7 and exhibits 3.3, 1.8, 7.3 times selective for Cbx7 over Cbx2/4/8 and 28-fold selective over the HP1 family member Cbx1. Our research provides several potent and partially selective inhibitors for Cbx2/4/7 that do not contain trimethyllysine. Our models and binding data suggest that the aromatic cages of Cbx7/Cbx4 can accommodate larger alkyl groups such as diisobutyl substitution on the lysine nitrogen.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThis work was funded by the West Coast Ride to Live, Prostate Cancer Canada, and Cancer Research Society of Canada. J.E.W. and F.H. are Canada Research Chairs.en_US
dc.identifier.citationSimhadri, C., Gignac, M. C., Anderson, C. J., Milosevich, N., Dheri, A., Prashar, N., Flemmer, R. T., Dev, A., Henderson, T. G., Douglas, S. F., Wulff, J. E., & Hof, F. (2016). Structure-activity relationships of Cbx7 inhibitors, including selectivity studies against other Cbx proteins. ACS Omega, 1(4), 541-551. https://doi.org/10.1021/acsomega.6b00120en_US
dc.identifier.urihttps://doi.org/10.1021/acsomega.6b00120
dc.identifier.urihttp://hdl.handle.net/1828/11860
dc.language.isoenen_US
dc.publisherACS Omegaen_US
dc.subjectpeptides and proteinsen_US
dc.subjectligandsen_US
dc.subjectinhibitorsen_US
dc.subjectselectivityen_US
dc.subjectscreening assaysen_US
dc.titleStructure–Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteinsen_US
dc.typeArticleen_US

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