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Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity - PubMed

  • ️Sat Jan 01 2011

. 2011 Jul 14;54(13):4928-32.

doi: 10.1021/jm200453n. Epub 2011 Jun 13.

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Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity

Donghang Cheng et al. J Med Chem. 2011.

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.

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Figures

Figure 1
Figure 1

CARM1-selective inhibitors used in this study.

Figure 2
Figure 2

Inhibitory activities of compounds 8a-l against CARM1 using PABP1 as a substrate, PRMT1 using NPL3 as a substrate, and SET7 using histone H3 as a substrate. The concentration of the compounds used in each in vitro methylation assay is shown.

Figure 3
Figure 3

Inhibitory activity of 7g, 8e, and 8l against CARM1 using PABP1, CA150, SMB, and histone H3 as substrates, and against a panel of PRMTs (PRMT1, PRMT3, PRMT5, and PRMT6) using indicated histone and/or non-histone substrates. The fluorographs are shown in the left panels, and the tritium count for each band is depicted in the right panels.

Figure 4
Figure 4

Inhibitory activities of 7g, 8e, and 8l against a panel of HKMTs (SET7, DOTL1, Suv39H1, and G9a) using the indicated histone and/or non-histone substrates.

Figure 5
Figure 5

Effects of increasing concentrations of 7g, 8e, and 8l on PSA promoter activity by luciferase assay in LNCaP cells, relative to a CMV-Renilla control (top panel), and on cell viability based on quantitation of the ATP present, which is an indicator of metabolically active cells, and is used to determine the viability of cells in culture (bottom panel). The results are presented as mean ± SD that were calculated from triplicate luciferase assays.

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