UNC1999

UNC1999 A chemical probe for EZH2/1

UNC1999 Cayman Chemical, Sigma and Tocris
UNC2400 (control for UNC1999)  Tocris
UNC2399 (biotinylated UNC1999) Tocris

  • overview
  • properties
  • selectivity profile
  • cell based assay data
  • references
overview

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. A collaboration between the SGC and the Center for Integrative Chemical Biology and Drug Discovery (CICBDD) at the University of North Carolina at Chapel Hill has resulted in the discovery of UNC1999. UNC1999 inhibits EZH2 with an IC50 of 2nM and is over 1000-fold selective for other HMTs except EZH1 (22-fold selectivity). UNC1999 inhibits H3K27 methylation in MCF10A cells with an IC50 of 124nM as measured by immunofluorescence. A dimethylated version, UNC2400, was also used as a negative control compound in key experiments.

properties

N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]-1-(propan-2-yl)-6-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-indazole-4-carboxamide

Click here to download the SD file

Physical and chemical properties
Molecular weight569.74
Molecular formulaC33H43N7O2
IUPAC nameN-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]-1-(propan-2-yl)-6-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-indazole-4-carboxamide
logP4.01
PSA95.39
  • SMILES
  • CCCC1C=C(C)NC(C=1CNC(c1cc(cc2c1cnn2C(C)C)c1ccc(nc1)N1CCN(CC1)C(C)C)=O)=O
  • InChi
  • InChI=1S/C33H43N7O2/c1-7-8-24-15-23(6)37-33(42)28(24)19-35-32(41)27-16-26(17-30-29(27)20-36-40(30)22(4)5)25-9-10-31(34-18-25)39-13-11-38(12-14-39)21(2)3/h9-10,15-18,20-22H,7-8,11-14,19H2,1-6H3,(H,35,41)(H,37,42)
  • InChiKey
  • InChIKey=DPJNKUOXBZSZAI-UHFFFAOYSA-N
selectivity profile

UNC1999 is selective for EZH2 over 15 other methyltransferases and proteins in other target classes

  • Less than 20% inhibition on 50 kinase targets @ 10 µM.
  • Less than 50% inhibition on 40 7TM targets @ 10 µM.
  • Greater than 50% inhibition of 4 7TM targets @ 10 µM.
    • H3 (Ki 300 nM), NET (Ki 1500nM), Sigma 1(Ki 4700 nM), Sigma 2 (Ki 65 nM)
    • No functional activity on H3, functional assay not available for Sigma 2
in vitro potency
cell based assay data

UNC1999 is Cellularly Active

A. Treatment of MCF10A cells for 3 days with UNC1999 shows a dose-related decrease in H3K27me3 which is unrelated to cell viability. 
B. UNC2400 did not show any dose-related decrease in H3K27me3.

UNC1999 Kills DB cells with Y641N mutation

DB cells harbor the EZH2 Y641N mutation

C. 8-day treatment of UNC1999 but not UNC2400 kills DB cells.
D. Western blotting of EZH2, total H3 and H3K27me3 following 3-day treatment of UNC1999 shows no change in H3 or EZH2, but significant change in H3K27me3

references

An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1
 

Kyle D. Konze, Anqi Ma, Fengling Li, Dalia Barsyte-Lovejoy, Trevor Parton, Christopher J.MacNevin, Feng Liu, Cen Gao, Xi-Ping Huang, Ekaterina Kuznetsova, Marie Rougie, Alice Jiang, Samantha G. Pattenden, Jacqueline L. Norris, Lindsey I. James, Bryan L Roth, Peter J. Brown, Stephen V. Frye, Cheryl H. Arrowsmith, Klaus M. Hahn, Gang Greg Wang, Masoud Vedadi, and Jian Jin.

ACS Chem. Biol., 2013, 8 (6), pp 1324–1334 

DOI: 10.1021/cb400133j • Publication Date (Web): 08 Apr 2013

pk properties
co-crystal structures
synthetic schemes
materials and methods
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