Toronto, ON (October 25, 2013) – The Structural Genomics Consortium (SGC) announced today that Janssen Pharmaceuticals NV has joined its group to partner in the investigation of epigenetics-based drug research, a new and burgeoning field in the development of future medicines.
By Aled Edwards, SGC CEO
At the SGC, we want to help stimulate the discovery of new medicines – yet we explicitly do not file for patents and promptly release information that is customarily kept secret until publication. How are we helping drug discovery by releasing our information promptly and without restriction? Patents are the key to protecting a drug’s market rights, and this provides the incentive for drug companies to take big financial risks…so how does making knowledge freely available help pharma? Isn’t this a non sequitur?
By Aled Edwards, SGC CEO
By Aled Edwards, SGC CEO
The origins of the Structural Genomics Consortium (SGC) can be traced back to 1999 when Rob Cooke (then at GlaxoWellcome) floated an idea past counterparts in other pharmaceutical companies as to whether a pre-competitive consortium in the field of structural biology was worth establishing. This was inspired by the scientific and organizational success of the SNP consortium (a public-private partnership formed to sequence single nucleotide polymorphisms, and place this information into the public domain, without restriction).
The prevailing view in biomedicine and drug discovery is that we need more “innovation”.
At the SGC, we (narrowly) interpret “innovation” to mean novel targets and mechanisms because we believe this sort of innovation will have the greatest impact on unmet medical needs.
The Structural Genomics Consortium (SGC) recently launched a new scientific public-private partnership in tuberculosis and malaria drug discovery: the Structure-guided Drug Discovery Coalition, SDDC. Participants to the Coalition include the Seattle Structural Genomics Center for Infectious Disease, the Midwest Center for Structural Genomics, the Center for Structural Genomics of Infectious Diseases, the Tuberculosis Structural Genomics Consortium, leading academic researchers in North America and Europe, and drug discovery teams from academia and industry.
This compound is available from Sigma, Tocris and Cayman Chemical
| Probe |
 |
A-366 |
A collaboration between the SGC and Abbvie has resulted in the discovery of A-366, a chemical Probe for G9a/GLP. A-366 is a potent inhibitor of G9a/GLP with IC50 3 nM and > 100-fold selectivity over other methyltransferases and other non-epigenetic targets. A-366 has been shown to inhibit H3K9 methylation in cells with an IC50 of 100 nM and exhibits minimal cellular toxicity compared with previous quinazoline-based probes.
A recent study by Wagner et al. (PMID: 26893353) showed that A-366 displaces H3K4me3 from Spindlin1 (2nd Tudor domain) with IC50 = 182.6 ± 9.1 nM.
| A-366 |
|
| 5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine |
| Physical and chemical properties for A-366 | |
| Molecular weight | 329.2 |
| Molecular formula | C19H27N3O2 |
| IUPAC name | 5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine |
| MollogP | 3.924 |
| PSA | 49.37 |
| No. of chiral centres | 0 |
| No. of rotatable bonds | 6 |
| No. of hydrogen bond acceptors | 4 |
| No. of hydrogen bond donors | 2 |
Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett. 2014 Jan 2;5(2):205-9
Sweis RF, Pliushchev M, Brown PJ, Guo J, Li F, Maag D, Petros AM, Soni NB, Tse C, Vedadi M, Michaelides MR, Chiang GG, Pappano WN.
The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia. PLoS ONE 10(7): e0131716. doi:10.1371/journal. pone.0131716. William N. Pappano, Jun Guo, Yupeng He, Debra Ferguson, Sujatha Jagadeeswaran, Donald J. Osterling, Wenqing Gao, Julie K. Spence, Marina Pliushchev, Ramzi F. Sweis, Fritz G. Buchanan, Michael R. Michaelides, Alexander R. Shoemaker, Chris Tse, Gary G. Chiang.
Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res. 2016 Feb 17.
Wagner T, Greschik H, Burgahn T, Schmidtkunz K, Schott AK, McMillan J, Baranauskienė L, Xiong Y, Fedorov O, Jin J, Oppermann U, Matulis D,Schüle R, Jung M.
Main features
INGELHEIM, Germany (6th May, 2013) – Today Boehringer Ingelheim announced that it has joined the Structural Genomics Consortium (SGC). The consortium intends to promote research into protein structures and epigenetics that could pave the way for the development of novel therapies for previously uncurable diseases.As a member of the SGC, Boehringer Ingelheim will help fund precompetitive drug research aimed at bringing new, more effective medicines to patients faster. The SGC is based at the Universities of Toronto, Canada, and Oxford, England.
This probe hydrochloride) is available from Sigma (including its negative control), Tocris (including its negative control) and Cayman Chemical (including its negative control).
| Probe | Negative control | |
 |
|  |
(R)-PFI-2 |
| (S)-PFI-2 |
A collaboration between the SGC and Pfizer has resulted in the discovery of (R)-PFI-2, a chemical Probe for SETD7. PFI-2 is a potent inhibitor of SETD7 with IC50 2 nM and 1000-fold selectivity over other methyltransferases and other non-epigenetic targets. PFI-2 has been shown to bind to SETD7 by ITC (Kd=18nM) and biotinylated PFI-2 interacts with SETD7 in pull-down studies. Its enantiomer (S)-PFI-2 is 500-fold less active making it an excellent negative control. Treatment of low-density MEFs with (R)-PFI-2 resulted in higher nuclear YAP levels indicating an effect on the Hippo pathway.
| Probe | Negative control | |
|
| |
(R)-PFI-2 |
| (S)-PFI-2 |
| Physical and chemical properties for (S)-PFI-2 | |
| Molecular weight | 499.2 |
| Molecular formula | C23H25F4N3O3S |
| MollogP | 3.504 |
| PSA | 70.67 |
| No. of chiral centres | 1 |
| No. of rotatable bonds | 8 |
| No. of hydrogen bond acceptors | 8 |
| No. of hydrogen bond donors | 2 |
| Physical and chemical properties for (R)-PFI-2 | |
| Molecular weight | 499.2 |
| Molecular formula | C23H25F4N3O3S |
| MollogP | 3.504 |
| PSA | 70.67 |
| No. of chiral centres | 1 |
| No. of rotatable bonds | 8 |
| No. of hydrogen bond acceptors | 8 |
| No. of hydrogen bond donors | 2 |
Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH. (R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12853-8. doi: 10.1073/pnas.1407358111. Epub 2014 Aug 18.
The probe UNC1999 is available from Cayman Chemical, Sigma and Tocris.
| Probe | Negative control | |
 |
|  |
UNC1999 |
| UNC2400 |
| Biotinylated UNC1999 |
 |
UNC2399 |
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.
| UNC1999 |
|
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 weight | 569.74 |
| Molecular formula | C33H43N7O2 |
| IUPAC name | 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 |
| logP | 4.01 |
| PSA | 95.39 |
UNC1999 is selective for EZH2 over 15 other methyltransferases and proteins in other target classes
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
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
