Pan-specific and partially selective dye-labeled peptidic inhibitors of the polycomb paralog proteins

Milosevich, Natalia; McFarlane, James; Gignac, Michael C.; Li, Janessa; Brown, Tyler; Wilson, Chelsea; Devorkin, Lindsey; Croft, Caitlin S.; Hof, Rebecca; Paci, Irina; Lum, Julian J.; Hof, Fraser

doi:10.1016/j.bmc.2019.115176

Cited by 7 publications

(14 citation statements)

References 27 publications

(53 reference statements)

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“…We started our efforts with modifications to previously reported CBX6-targeting peptidic inhibitors, [19,22] and chose to screen each compound against CBX1/6/7/8. This panel was chosen in order to efficiently obtain data on CBX6-and CBX8-selectivity over CBX7, which is the CBX that intrinsically binds ligands most strongly.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous report on CBX6 inhibition included the initial scaffold 1, the promiscuous inhibitor 2, CBX6selective inhibitor 3 that is 6-90-fold selective for CBX6 over CBX1, 7 and 8, 4 the dye-free analog of 2; and compound 5 the dye-free analog of 3 (Figure 1). [19,22] As a first step towards making lower molecular weight compounds, we investigated 1, which is an analog of 2 that lacks the C-terminal Glu residue and dye label (Figure 1, Table 1). Compound 1 is 10-fold selective for CBX7 over CBX1 and 6-and 29-fold selective over CBX6 and CBX8, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Removal of the FITC-labeled lysine on the scaffold containing the (-2) valine residue (2 compared to 4) resulted in a 20-, 40-and 3-fold decrease in binding to CBX6, CBX7 and CBX8, respectively. [19,22] We knew from previous reports that removal of the FITC dye label makes these compounds significantly less potent. From the current experiments we can also see that the FITC removal affects CBX6 and CBX8 binding differently.…”

Section: Resultsmentioning

confidence: 99%

“…[b] Estimated value because IC50 is outside of linear range of assay. [22][23] [c] Not tested Substitution of the methylisoxazole N-cap gave large improvements in potency. We synthesized compounds 20 and 21, containing a propyl substitution in the 5-position of the isoxazole ring (Figure 5, Table 5).…”

Section: Resultsmentioning

confidence: 99%

“…[c] Estimated value because IC50 is outside of linear range of assay. [22][23] Larger hydrophobic substitutions in the (-2) position of the ligand allow for CBX8 selective inhibitors. We synthesized analogs of compound 11 containing a cyclopropyl, cyclopentyl and sec-butyl group at the (−2) position (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

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Polycomb Paralog Chromodomain Inhibitors Active Against Both CBX6 and CBX8

Milosevich¹,

Wilson²,

Brown³

et al. 2021

Preprint

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Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the –2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cell-based studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line. This report includes data on inhibitor design, inhibitor synthesis, compound characterization by LCMS, compound activity by fluorescence polarization, analysis of structure-activity relationships, rhabdoid tumor cell line activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Polycomb Paralog Chromodomain Inhibitors Active Against Both CBX6 and CBX8

Milosevich¹,

Wilson²,

Brown³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Polycomb Paralog Chromodomain Inhibitors Active against Both CBX6 and CBX8**

et al. 2021

Self Cite

View full text Add to dashboard Cite

Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing either the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 (H3) via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the À 2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cellbased studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line.

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Unresolved questions regarding cellular cysteine sources and their possible relationships to ferroptosis

Arnér,

Schmidt

2024

Advances in Cancer Research

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Pan-specific and partially selective dye-labeled peptidic inhibitors of the polycomb paralog proteins

Cited by 7 publications

References 27 publications

Polycomb Paralog Chromodomain Inhibitors Active Against Both CBX6 and CBX8

Polycomb Paralog Chromodomain Inhibitors Active Against Both CBX6 and CBX8

Polycomb Paralog Chromodomain Inhibitors Active against Both CBX6 and CBX8**

Unresolved questions regarding cellular cysteine sources and their possible relationships to ferroptosis

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