02.08.2013

Why put science in the public domain?

by: SGC

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?

02.08.2013

The launch of the SGC

by: SGC

By Aled Edwards, SGC CEO

02.08.2013

How did the SGC get formed?

by: SGC

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).

02.08.2013

Biotech and Innovation

by: SGC

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.

16.07.2013

SGC launches the Structure-guided Drug Discovery Coalition (SDDC) for tuberculosis and malaria

by: SGC

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.

A-366 A chemical Probe for G9a/GLP

This compound is available from Sigma, Tocris and Cayman Chemical

  • overview
  • properties
  • selectivity profile
  • cell based assay data
  • references
  • co-crystal structures
overview
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. 

properties
A-366
5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine
Physical and chemical properties for A-366
Molecular weight329.2
Molecular formulaC19H27N3O2
IUPAC name5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine
MollogP3.924
PSA49.37
No. of chiral centres0
No. of rotatable bonds6
No. of hydrogen bond acceptors4
No. of hydrogen bond donors2
  • SMILES:
  • COC1=CC2=C(N=C(N)C23CCC3)C=C1OCCCN4CCCC4
  • InChI:
  • InChI=1S/C19H27N3O2/c1-23-16-12-14-15(21-18(20)19(14)6-4-7-19)13-17(16)24-11-5-10-22-8-2-3-9-22/h12-13H,2-11H2,1H3,(H2,20,21)
  • InChIKey:
  • BKCDJTRMYWSXMC-UHFFFAOYSA-N
selectivity profile

in vitro potency
cell based assay data
references

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.

pk properties
co-crystal structures

Please wait whilst the interactive viewer is loaded!



Main features

synthetic schemes
materials and methods
06.05.2013

Boehringer-Ingelheim joins SGC

by: SGC

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.

(R)-PFI-2 A probe for SETD7

This probe hydrochloride) is available from Sigma (including its negative control), Tocris (including its negative control) and Cayman Chemical (including its negative control).

  • overview
  • properties
  • selectivity profile
  • cell based assay data
  • references
  • co-crystal structures
overview
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.

properties
Probe Negative control

 

(R)-PFI-2

 

(S)-PFI-2

Physical and chemical properties for (S)-PFI-2
Molecular weight499.2
Molecular formulaC23H25F4N3O3S
MollogP3.504
PSA70.67
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors8
No. of hydrogen bond donors2
Physical and chemical properties for (R)-PFI-2
Molecular weight499.2
Molecular formulaC23H25F4N3O3S
MollogP3.504
PSA70.67
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors8
No. of hydrogen bond donors2
  • SMILES:
  • (S)-PFI-2: FC(F)(F)C1=CC(C[C@H](NS(C2=CC(F)=C3CNCCC3=C2)(=O)=O)C(N4CCCC4)=O)=CC=C1
  • (R)-PFI-2: FC(F)(F)C1=CC(C[C@@H](NS(C2=CC3=C(C(F)=C2)CNCC3)(=O)=O)C(N4CCCC4)=O)=CC=C1
  • InChI:
  • (S)-PFI-2: InChI=1S/C23H25F4N3O3S/c24-20-13-18(12-16-6-7-28-14-19(16)20)34(32,33)29-21(22(31)30-8-1-2-9-30)11-15-4-3-5-17(10-15)23(25,26)27/h3-5,10,12-13,21,28-29H,1-2,6-9,11,14H2/t21-/m0/s1
  • (R)-PFI-2: InChI=1S/C23H25F4N3O3S/c24-20-13-18(12-16-6-7-28-14-19(16)20)34(32,33)29-21(22(31)30-8-1-2-9-30)11-15-4-3-5-17(10-15)23(25,26)27/h3-5,10,12-13,21,28-29H,1-2,6-9,11,14H2/t21-/m1/s1
  • InChIKey:
  • (S)-PFI-2: JCKGSPAAPQRPBW-NRFANRHFSA-N
  • (R)-PFI-2: JCKGSPAAPQRPBW-OAQYLSRUSA-N
selectivity profile

in vitro potency
cell based assay data
references

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.

pk properties
co-crystal structures

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Main features

  • PFI-2 efficiently exploits the substrate binding site of SETD7.
  • PFI-2 interacts directly with the departing methyl group of SAM.
  • PFI-2 occupies the lysine binding site of SETD7.
synthetic schemes
materials and methods

UNC1999 A chemical probe for EZH2/1

The probe UNC1999 is available from Cayman Chemical, Sigma and Tocris.

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

properties
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 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
  • CCCC(C=C(N1)C)=C(CNC(C2=CC(C3=CC=C(N4CCN(C(C)C)CC4)N=C3)=CC5=C2C=NN5C(C)C)=O)C1=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
02.04.2013

Novel structure of a human membrane enzyme sheds light on molecular mechanisms of rare ageing disorders and metabolic syndromes

by: SGC

Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins involved in the building and maintenance of the nuclei of cells. Severe laminopathies such as the premature ageing syndrome pregeria leads to death in the teens from heart disease and other symtoms normally found in people in their 80s. The structure of the nucleus is maintained by a class of proteins called lamins. When one of these proteins, prelamin A is not properly processed by an enzyme ZMPSTE24, laminopathies occur.

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