UNC1999 is a potent, orally bioavailable and selective inhibitor of EZH2 and EZH1 with IC50 of 2 nM and 45 nM in cell-free assays, respectively, showing >1000-fold selectivity over a broad range of epigenetic and non-epigenetic targets.
The first orally bioavailable inhibitor against wild-type and mutant EZH2 as well as EZH1.
UNC1999 is highly potent for both EZH2 Y641N and EZH2 Y641F mutants in vitro. UNC1999 causes concentration-dependent reductions of H3K27me3 in MCF10A cells with IC50 of 124 nM , while shows low cellular toxicity. UNC1999 displays potent, concentration-dependent inhibition of cell proliferation with EC50 of 633 nM in a DLBCL cell line harboring the EZH2Y641N mutant. In addition, biotinylated UNC1999 enriches EZH2 from HEK293T cell lysates, and thus may be used in chemoproteomics studies.
Treatment of UNC1999 (150 and 50 mg/kg, i.p.) results in the plasma concentrations of UNC1999 above its cellular IC50 over 24 hours in vivo. In addition, UNC1999 is also orally bioavailable in mice, which makes chronic animal studies more practical and convenient.
UNC1999 (1431612-23-5) is an orally bioavailable, highly selective inhibitor of both wild-type and mutant EZH1 and EZH2 lysine methyltransferases (IC50‘s = 45 nM and 2 nM respectively).1Inhibition of EZH2 with UNC1999 enhanced the efficacy of gefitinib (Cat.# 10-1148) in suppressing the proliferation of colon cancer cells
UNC1999 acts as an inhibitor for lysine methyltransferases EZH2 and EZH1 which have been implicated in the expression of various cancers.
The histone H3 lysine 27 (H3K27) methyltransferase EZH2 plays an important role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. UNC1999 is a cell-permeable EZH2 inhibitor (IC50 = 2 nM) that is 22-fold selective over EZH1 and >1,000-fold selective over other histone methytranferases. UNC1999 has been shown to inhibit H3K27 methylation in MCF10A cells with an IC50 value of 124 nM.[Cayman Chemical]
The polycomb repressive complex 2 (PRC2), which represses gene expression through methylation of histone H3 on lysine 27 (H3K27), contains either EZH1 or EZH2 as its catalytic subunit, with EZH1 being found in both dividing and non-dividing cells, whereas EZH2 is only found in actively dividing cells. UNC1999 is an orally bioavaliable selective inhibitor of both EZH2 and EZH1 lysine methyltransferases with IC50 < 10 nM for EZH2 and 45 nM for EZH1. UNC1999 potently inhibited both wild-type and mutant Y641N EZH2 methyltransferase activity with less than a 5-fold difference in potency, and selectively killed diffused large B cell lymphoma (DLBCL) cells bearing Y641 point mutations. It was selective for EZH2 and EZH1 over 15 other lysine, arginine and DNA methyltransferases. UNC1999 is competitive with the cofactor S-adenosylmethionine (SAM) and non-competitive with the peptide substrate. Because it inhibits both EZH2 and EZH1, UNC1999 has potential advantages over EZH2 selective inhibitors in the disease settings where both PRC2 – EZH2 and PRC2 – EZH1 contribute to the methylation of H3K27. For full characterization details, please visit the UNC1999 probe summary on the Structural Genomics Consortium (SGC) website.UNC2400 is the negative control for the active probe, UNC1999. To request a sample of the negative control from the SGC, click here.To learn about other SGC chemical probes for epigenetic targets, visit sigma.com/sgc
A single intraperitoneal (IP) injection of UNC1999 at 15, 50, or 150 mg/kg achieved high Cmax (9,700-11,800 nM) and exhibited dose linearity in male Swiss albino mice. Both the 150 and 50 mg/kg IP doses resulted in the plasma concentrations of UNC1999 above its cellular IC50 over the entire 24 h period while the 15 mg/kg IP dose led to the plasma concentrations of UNC1999 above its cellular IC50 for approximately 12 h. We next examined whether UNC1999 is orally bioavailable and are pleased to find that a single 50 mg/kg oral dose of UNC1999 achieved high Cmax (4,700 nM) and good exposure levels in male Swiss albino mice. The plasma concentrations of UNC1999 are maintained above its cellular IC50 for approximately 20 h following this single oral dose. It is worth noting that all doses including the 150 mg/kg IP dose are well tolerated by all test mice, and no adverse effects are observed[1].
UNC1999 inhibits EZH2 and EZH1 histone-lysine N-methyltransferase activity through competitive inhibition of the cofactor S-Adenosyl-l-methionine. The UNC1999 inhibitor displays potent specificity relative to other histone methyltransferases. IC50 values for EZH2 and EZH1 are 2 nM and 45 nM, respectively. Research studies demonstrate that UNC1999 effectively blocks histone H3 lysine 27 methylation. UNC1999 induces anti-proliferation, cell differentiation, and apoptosis, while exhibiting low cellular toxicity.
[1] KYLE D. KONZE. An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1[J]. ACS Chemical Biology, 2013, 8 6: 1324-1334. DOI:
10.1021/cb400133j[2] BRYSON W KATONA. EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells.[J]. Cancer Biology & Therapy, 2014, 15 12: 1677-1687. DOI:
10.4161/15384047.2014.972776
