EPZ-6438

SAM competitive inhibitor of EZH2

Structure

Information

  • EZH2
  • SAM competitive inhibitor
  • 30-1,000 nM

In Vitro Validations

Uniprot ID: Q15910
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: Ki
Potency Value: EZH2 2.5 nM
Potency Assay: PRC2-containing enzyme assay. The Ki was comparable for wild-type enzyme and for the following mutants: A677G, A687V, Y641F, Y641H, Y641N, and Y641S.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Histone-lysine N-methyltransferase EZH2, KMT6, EZH ...

DOI Reference: 10.1073/pnas.1303800110

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): EPZ-6438 is 35-fold selective for EZH2 over EZH1 and 4,500-fold selective over all other protein methyltransferases tested (CARM1,DOT1L, EHMT1, EHMT2, PRMT1, PRMT3, PRMT5, PRMT6, PRMT8, SETD7, SMYD2, SMYD3, WHSC1 WHSC1L1).
Probe Selectivity in Vitro:

Not available

Potency assay, off target (cells): No activity was detected by assessing other histone substrates (H3K9, H3K4, H3K36 and H3K79)
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The compound shows good potency in the inhibition of H3K27 trimethylation in multiple cell lines, making it a potentially useful tool. Note that 4 days of dosing is required. Note also that the compound shows EZH1 (off-target) activity with ~35 fold selectivity. Data on broad selectivity would be useful; although the excellent potency/low concentration required in cells somewhat mitigates against concerns. In vivo experiments require high doses over an extended period (3-4 weeks), despite the stated "good oral bioavailability" of this compound. Therefore, I cannnot be entirely certain that the effects observed in the in vivo experiments are due solely to the compound's EZH2 activity. At the high concentrations used, activity against EZH1 or other unknown targets could be involved. No detailed pharmacokinetic information is provided (only concentrations at 2 time points after 21 days).

(last updated: 15 Aug 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This compound shows high in vitro potency for wild-type EZH2 (Ki = 2.5 nM) and for EZH2 mutations (Y641F, C, H, N, S and A677G); SAM competitive and non-competitive with peptide substrate; ca. 35-fold selective for EZH2 over EZH1 and more than 4,500-fold selective relative to other PMTs, including G9a, GLP, SETD7, SMYD2, SMYD3, MMSET, WHSC1L1, PRMTs, DOT1L. The compound is potent in cellular antiproliferation assays, displayed efficacy in a xenograft model (dosed for 28 days) and was well-tolerated, making it an interesting tool compound.

(last updated: 23 Dec 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

EPZ-6438 is a potent, SAM-competitive inhibitor of wild-type and all known mutants of EZH2 with biochemical selectivity over EZH1 and other histone methyl transferases. Potent target engagement in cells (<5 nM) has been demonstrated by inhibition of the H3K27Me3 methylation mark, but this requires extended incubation (4 days). Selectivity in cells is shown by the lack of effect on other H3 histone methylation marks. No other off-target pharmacology data is available, and I cannot exclude off-target effects in cells, although this is mitigated by the selective apoptotic effects demonstrated in SMARCB1-deficient, EZH2-dependent cells (antiproliferation IC50s ca. 100 nM) compared to SMARCB1-proficient cells. I suggest the use of 30-1,000 nM concentrations in cell-based experiments, and the use of an orthogonal, EZH2-selective probe in parallel (e.g., GSK343). Dose-dependent anti-tumour efficacy and inhibition of H3K27Me3 in human tumour xenografts by EPZ-6438 has been shown following high oral doses for extended periods. Detailed in vivo pharmacokinetic parameters are not available but would be useful to interpret the in vivo biology. I cannot exclude the possibility of off-target effects at the high doses.

(last updated: 16 Jan 2017 )