LLY-507 A chemical probe for SMYD2 protein lysine methyltransferase

This probe is available from Cayman Chemical, Tocris and Sigma

For any inquiries please contact proberequests@thesgc.org.

group new

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 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

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

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).

Co-crystal structures

Please wait whilst the interactive viewer is loaded!

PDB: 4WUY
Main features
1. LLY-507 with SAH
2. Overlay with peptide structure showing LLY-507 in peptide site
3. LLY-507 key interactions

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.