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1.
Scheme 1

Scheme 1. Synthetic routes for preparing designed compounds. From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

Synthesis of compounds in (A), (B), and (C).

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

2.
Figure 5

Figure 5. Compound 46 a close analog of compound 17, has no inhibitory activity against PRMT4 and PRMT6. From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

NI: no inhibition.

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

3.
Figure 2

Figure 2. Selectivity of 17 against methyltransferases. From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

Selectivity of 17 against a panel of 25 PKMTs and DNMTs was determined at two compound concentrations of 10 μM (■) and 50 μM ().

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

4.
Figure 1

Figure 1. (A) Structure and potency of compounds 1 (PRMT4 inhibitor), 2 (PRMT6 selective inhibitor), and 3 (selective type I PRMT inhibitor). (B) Structure and potency of compound 4, a fragment-like inhibitor of type I PRMTs. (C) X-ray cocrystal structure of compound 4 (cyan) in the complex with PRMT6 (gray) and SAH (green) (PDB: 5EGS). From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

The key H-bond interactions are shown in yellow dotted lines.

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

5.
Figure 4

Figure 4. The effect of 17 on inhibiting PRMT6 and PRMT4 in cells. From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

(A) Compound 17 inhibits PRMT6 methyltransferase activity in HEK293 cells. HEK293 cells were transfected with FLAG-tagged PRMT6 (wt) or its catalytically inactive mutant V86K/D88A (mut) and treated with 17 at indicated concentrations for 20 h. H3R2me2a levels were determined by Western blot. The graphs represent nonlinear fits of H3R2me2a signal intensities normalized to total histone H3. The results are MEAN ± SEM of 3 replicates. (B) Compound 17 inhibits endogenous PRMT4 methyltransferase activity in HEK293 cells. HEK293 cells were treated with 17 at indicated concentrations for 72 h and Med12-Rme2a levels were determined by Western blot. The graphs represent nonlinear fits of Med12-Rme2a signal intensities normalized to total Med12. The results are MEAN ± SEM of 3 replicates.

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

6.
Figure 3

Figure 3. Binding confirmation and MOA of 17. From: Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

(A) Isothermal titration calorimetry (ITC) was used to confirm binding of 17 to PRMT4 with a Kd of 100 nM (B) and to PRMT6 with a Kd of 87 ± 35 nM. ITC experiments for PRMT4 and PRMT6 were performed in duplicate and triplicate, respectively. Differential scanning fluorimetry (DSF) was also used to confirm the binding of 17 to PRMT4 (C) and PRMT6 (D). Experiments were performed (•) in the absence of any compound as a negative control and in the presence of (○) 100 μM SAH as a positive control with PRMT4 (ΔTm of 4 °C) and PRMT6 (ΔTm of 8.4 °C). Presence of (▲) 200 μM 17 resulted in stabilization of both proteins with ΔTm of 3.3 and 11 °C for PRMT4 and PRMT6, respectively. Presence of (□) 100 μM SAM plus 200 μM 17 had the highest effect with ΔTm of 13 and 21 °C for PRMT4 and PRMT6, respectively. The inflection point of each transition curve is considered melting temperature (Tm) and the increase in Tm is an indication of binding. The IC50 values for 17 with PRMT4 and PRMT6 was unchanged when determined under various peptide (E) and SAM (F) concentrations suggesting an apparent noncompetitive pattern of inhibition

Yudao Shen, et al. J Med Chem. ;59(19):9124-9139.

CitationFull text

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