TY - JOUR
T1 - Discovery of the First-in-Class G9a/GLP Covalent Inhibitors
AU - Park, Kwang Su
AU - Xiong, Yan
AU - Yim, Hyerin
AU - Velez, Julia
AU - Babault, Nicolas
AU - Kumar, Prashasti
AU - Liu, Jing
AU - Jin, Jian
N1 - Funding Information:
This research was supported in part by Grant R01HD088626 (to J.J.) from the National Institutes of Health (NIH), Levo Therapeutics, and an endowed professorship by the Icahn School of Medicine at Mount Sinai (to J.J.). This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG Grants 1S10OD025132 and 1S10OD028504. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We also thank the staff at the 24-ID-E beamline of the Advanced Photon Source at Argonne National Laboratory for facilitating X-ray data collection. We thank Dr. Jithesh Kottur for helping with crystallographic refinement.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/8/11
Y1 - 2022/8/11
N2 - The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.
AB - The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.
UR - http://www.scopus.com/inward/record.url?scp=85134836254&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c00652
DO - 10.1021/acs.jmedchem.2c00652
M3 - Article
C2 - 35763668
AN - SCOPUS:85134836254
VL - 65
SP - 10506
EP - 10522
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -