This probe is available from Cayman Chemical and Sigma.
| Probe | Negative control | |
 |
|  |
LLY-507 (IC50 < 15 nM) |
| SGC705 (IC50> 10,000 nM) |
A collaboration between the SGC and Eli Lilly and Company has resulted in the discovery of LLY-507, a chemical probe for SMYD2 (a protein lysine methyltransferase). LLY-507 is a potent inhibitor of SMYD2 with in vitro IC50 <15 nM and >100-fold selectivity over other methyltransferases and other non-epigenetic targets. LLY-507 has been shown to inhibit p53K370 monomethylation in cells with an IC50 ~600 nM.
Note: After LLY-507 was released, off-target screening (in addition to those presented in the publication, doi:10.1074/jbc.M114.626861) was done. Here is a copy of the report from a functional screen of LLY-507 and its control SGC705 in the NIMH Psychoactive Drug Screening Program (PDSP). This report clearly shows more than 50% inhibition of a number of targets.
| Probe | Negative control | |
|
| |
LLY-507 (IC50 < 15 nM) |
| SGC705 (IC50> 10,000 nM) |
| Physical and chemical properties for LLY-507 | |
| Molecular weight | 574.3 |
| Molecular formula | C36H42N6O |
| IUPAC name | 5-(2-(4-(2-(9-methyl-7-aza-bicyclo[4.3.0]nona-1(6),2,4,8-tetraen-7-yl)-ethyl)-piperazin-1-yl)-phenyl)-3-((3-(pyrrolidin-1-yl)-propylamino)-formyl)-benzonitrile |
| MollogP | 5.891 |
| PSA | 54.28 |
| No. of chiral centres | 0 |
| No. of rotatable bonds | 12 |
| No. of hydrogen bond acceptors | 5 |
| No. of hydrogen bond donors | 1 |
| Physical and chemical properties for SGC705 (Negative Control) | |
| Molecular weight | 573.3 |
| Molecular formula | C37H43N5O |
| IUPAC name | 3-((3-cyclopentyl-propylamino)-formyl)-5-(2-(4-(2-(9-methyl-7-aza-bicyclo[4.3.0]nona-1(6),2,4,8-tetraen-7-yl)-ethyl)-piperazin-1-yl)-phenyl)-benzonitrile |
| MollogP | 7.504 |
| PSA | 50.49 |
| No. of chiral centres | 0 |
| No. of rotatable bonds | 12 |
| No. of hydrogen bond acceptors | 4 |
| No. of hydrogen bond donors | 1 |
Effect of LLY-507 on the activity of 27 protein methyltransferases as well as DNMT1.
Mechanism of Action
Cellular Activity
Dose dependent inhibition of p53 K370 me1 by LLY-507 in KYSE-150 cells stably expressing SMYD2 as measured by a Meso Scale Discovery sandwich ELISA assay (IC50 = 0.6 microM).
LLY-507, a Cell-Active, Potent and Selective Inhibitor of Protein Lysine Methyltransferase SMYD2 J. Biol. Chem. doi:10.1074/jbc.M114.626861
Hannah Nguyen, Abdellah Allali-Hassani, Stephen Antonysamy, Shawn Chang, Lisa Hong Chen, Carmen Curtis, Spencer Emtage, Li Fan, Tarun Gheyi, Fengling Li, Shichong Liu, Joseph R. Martin, David Mendel, Jonathan B. Olsen, Laura Pelletier, Tatiana Shatseva, Song Wu, Feiyu Fred Zhang, Cheryl H. Arrowsmith, Peter J. Brown, Robert M. Campbell, Benjamin A. Garcia, Dalia Barsyte-Lovejoy, Mary Mader and Masoud Vedadi.
PDB: 4WUY
Main features
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.
