2. Academic Validation
  3. Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

  • Bioorg Med Chem. 2017 Aug 15;25(16):4414-4423. doi: 10.1016/j.bmc.2017.06.021.
Yan Xiong 1,  Fengling Li 2,  Nicolas Babault 1,  Hong Wu 2,  Aiping Dong 2,  Hong Zeng 2,  Xin Chen 1,  Cheryl H Arrowsmith 3,  Peter J Brown 2,  Jing Liu 1,  Masoud Vedadi 4,  Jian Jin 5
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
  • 4 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: [email protected].
  • 5 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: [email protected].
PMID: 28662962 DOI: 10.1016/j.bmc.2017.06.021
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.

Keywords

G9a; GLP; Inhibitor; Quinazoline; Quinoline.

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