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. 2022 Apr 28;65(17):11574–11606. doi: 10.1021/acs.jmedchem.2c00252

Table 2. Inhibitory Activities of Compounds 12a–12h against Various PRMTs.

  IC50 (μM)a,b
 selectivity index for PRMT4 vs other PRMTsc
  
no. PRMT1 PRMT3 PRMT4 PRMT5 PRMT6 PRMT7 PRMT8 PRMT1 PRMT3 PRMT5 PRMT6 PRMT7 PRMT8 LEd
12a 32.27 (0.5)e 57.19 13.84 52.13 72.77 0.32 8.29 2 4 4 5 0.02 1 0.14
12b 11.67 (0.43)e 43.41 2.14 76.7 >100 0.55 18.68 5 20 36 >47 0.26 9 0.18
12c 8.46 (0.3)e 21.26 0.42 51.41 >100 0.22 5.87 20 51 122 >238 0.52 14 0.19
12d 0.86 12.2 0.068 2.6 47 0.41 3.82 13 179 38 691 6 56 0.21
12e 2.6 12.4 0.176 3.38 35.6 0.631 5.84 15 70 19 202 4 33 0.20
12f 4.86 10.5 0.0097 0.115 22.7 0.226 6 501 1082 12 2340 23 619 0.24
12g 1.80 13.3 0.0084 0.778 4.34 4.68 1.41 214 1583 93 517 557 168 0.24
12h 0.835 4.05 0.0032 1.46 1.75 1.68 1.95 261 1266 456 547 525 609 0.25
a

Compounds were tested in 10-concentration IC50 mode with threefold serial dilutions starting at 100 μM. Data were analyzed with GraphPad Prism software (version 6.0) for IC50 curve fitting.

b

Unless differently indicated, the values were obtained in a radioisotope-based filter assay, using 5 μM histone H4 (for PRMT1, PRMT3, and PRMT8), histone H3 (for PRMT4), histone H2A (for PRMT5), or GST-GAR (for PRMT6 and PRMT7) as the substrate and S-adenosyl-l-[methyl-3H]methionine (1 μM) as methyl donor.

c

Selectivity index for PRMT4 over the specified PRMT, calculated as the ratio between the IC50 against the specified PRMT and the IC50 against PRMT4 and rounded to the nearest integer.

d

Ligand efficiency (LE) for PRMT4 calculated from IC50 as a surrogate for KD.

e

Obtained in the AlphaLISA assay, using human recombinant PRMT1 (0.9 nM, final concentration). Histone H4 (1–21) peptide, biotinylated (100 nM, final concentration), and SAM (2 μM, final concentration) were used as the substrate and cofactor, respectively.