5VSC

Structure of human G9a SET-domain (EHMT2) in complex with inhibitor 13

Summary for 5VSC

• Entry DOI: 10.2210/pdb5vsc/pdb
• Related: 5VSD 5VSE 5VSF
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: protein-small molecule inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q96KQ7
• Total number of polymer chains: 2
• Total formula weight: 65533.10

Authors

Babault, N.,Xiong, Y.,Liu, J.,Jin, J. (deposition date: 2017-05-11, release date: 2017-07-12, Last modification date: 2023-10-04)

Primary citation

Xiong, Y.,Li, F.,Babault, N.,Wu, H.,Dong, A.,Zeng, H.,Chen, X.,Arrowsmith, C.H.,Brown, P.J.,Liu, J.,Vedadi, M.,Jin, J.
Structure-activity relationship studies of G9a-like protein (GLP) inhibitors.
Bioorg. Med. Chem., 25:4414-4423, 2017

PubMed Abstract: Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.

PubMed: 28662962
DOI: 10.1016/j.bmc.2017.06.021

Experimental method

X-RAY DIFFRACTION (1.4 Å)