LLY-507 (multiple off-targets)

LLY-507 (multiple off-targets) A chemical probe for SMYD2 protein lysine methyltransferase

This probe is available from Cayman Chemical, Tocris and Sigma

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

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. 

properties


LLY-507


SGC705
(negative control)

Physical and chemical properties for LLY-507
Molecular weight574.3
Molecular formulaC36H42N6O
IUPAC name5-(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
MollogP5.891
PSA54.28
No. of chiral centres0
No. of rotatable bonds12
No. of hydrogen bond acceptors5
No. of hydrogen bond donors1
Physical and chemical properties for SGC705 (Negative Control)
Molecular weight573.3
Molecular formulaC37H43N5O
IUPAC name3-((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
MollogP7.504
PSA50.49
No. of chiral centres0
No. of rotatable bonds12
No. of hydrogen bond acceptors4
No. of hydrogen bond donors1
  • SMILES:
  • LLY-507: Cc1cn(CCN2CCN(CC2)c2ccccc2c2cc(C#N)cc(c2)C(NCCCN2CCCC2)=O)c2ccccc12
  • SGC705: Cc1cn(CCN2CCN(CC2)c2ccccc2c2cc(C#N)cc(c2)C(NCCCC2CCCC2)=O)c2ccccc12
  • InChI:
  • LLY-507: InChI=1S/C36H42N6O/c1-28-27-42(34-11-4-2-9-32(28)34)22-19-40-17-20-41(21-18-40)35-12-5-3-10-33(35)30-23-29(26-37)24-31(25-30)36(43)38-13-8-16-39-14-6-7-15-39/h2-5,9-12,23-25,27H,6-8,13-22H2,1H3,(H,38,43)
  • SGC705: InChI=1S/C37H43N5O/c1-28-27-42(35-14-6-4-12-33(28)35)22-19-40-17-20-41(21-18-40)36-15-7-5-13-34(36)31-23-30(26-38)24-32(25-31)37(43)39-16-8-11-29-9-2-3-10-29/h4-7,12-15,23-25,27,29H,2-3,8-11,16-22H2,1H3,(H,39,43)
  • InChIKey:
  • LLY-507: PNYRDVBFYVDJJI-UHFFFAOYSA-N
  • SGC705: UZLKKMNSZHUBDI-UHFFFAOYSA-N
selectivity profile

Effect of LLY-507 on the activity of 27 protein methyltransferases as well as DNMT1.

Mechanism of Action

in vitro potency
cell based assay data

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).

references

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.

pk properties
co-crystal structures

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PDB: 4WUY
Main features

synthetic schemes
materials and methods
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