The Jian Jin lab in the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina – Chapel Hill (UNC – CH) has two main research areas: (1) discovering chemical probes for histone methyltransferases (HMTs); and (2) creating functionally selective ligands of G protein-coupled receptors (GPCRs).

Discovery of Chemical Probes for HMTs

Post-translational modifications (PTMs) of histones play a critical role in diverse biological processes including chromatin compaction, gene expression, transcriptional regulation, and cell differentiation. Among a myriad of PTMs, histone methylation catalyzed by HMTs has been increasingly recognized as a major signaling mechanism in eukaryotic cells. HMTs (also known as protein methyltransferases (PMTs)) are divided into two categories: lysine methyltransferases (PKMTs), which catalyze mono-, di-, and/or trimethylation of lysine residues of histones and other proteins, and arginine methyltransferases (PRMTs), which catalyze mono- and/or asymmetric or symmetric dimethylation of arginine residues of histones and non-histone proteins. To date, more than 50 HMTs have been identified. Mounting evidence suggests that HMTs, the methyl “writers” of the histone code, play crucial roles in various human diseases.

Despite the importance of HMTs in human diseases, very few high quality, well-characterized chemical probes of HMTs have been reported. Since August 2008, the Jin lab has taken a target-class approach to systematically creating chemical probes for HMTs. Our recent publications in this area include:

1. Vedadi, M.; Barsyte-Lovejoy, D.; Liu, F.; Rival-Gervier, S.; Allali-Hassani, A.; Labrie, V.; Wigle, T. J.; DiMaggio, P. A.; Wasney, G. A.; Siarheyeva, A.; Dong, A.; Tempel, W.; Wang, S.-C.; Chen, X.; Chau, I.; Mangano, T.; Huang, X.-P.; Simpson, C. D.; Pattenden, S. G.; Norris, J. L.; Kireev, D. B.; Tripathy, A.; Edwards, A.; Roth, B. L.; Janzen, W. P.; Garcia, B. A.; Petronis, A.; Ellis, J.; Brown, P. J.; Frye, S. V.; Arrowsmith, C. H.*; Jin, J.* “A Chemical Probe Selectively Inhibits G9a and GLP Methyltransferase Activity in Cells” Nature Chemical Biology, 2011, 7, 566-574. (Highlighted by News and Views: Nature Chemical Biology, 2011, 7, 499-500; SciBX, 2011, 4(31), doi:10.1038/scibx.2011.890; and UNC Endeavors Magazine, October 2011 issue).
2. Liu, F.; Barsyte-Lovejoy, D.; Allali-Hassani, A.; He, Y.; Herold, J. M.; Chen, X.; Yates, C. M.; Frye, S. V.; Brown, P. J.; Huang, J.; Vedadi, M.; Arrowsmith, C. H.; Jin, J.*  “Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines” J. Med. Chem. 2011, 54, 6139-6150.
3. Liu, F.; Chen, X.; Allali-Hassani, A.; Quinn, A. M.; Wigle, T. J.; Wasney, G. A.; Dong, A.; Senisterra, G.; Chau, I.; Siarheyeva, A.; Norris, J. L.; Kireev, D. B.; Jadhav, A.; Herold, J. M.; Janzen, W. P.; Arrowsmith, C. H.; Frye, S. V.; Brown, P. J.; Simeonov, A.; Vedadi, M.; Jin, J.* “Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines” J. Med. Chem. 2010, 53, 5844-5857.
4. Liu, F.; Chen, X.; Allali-Hassani, A.; Quinn, A. M.; Wasney, G. A.; Dong, A.; Barsyte, D.; Kozieradzki, I.; Senisterra, G.; Chau, I.; Siarheyeva, A.; Kireev, D. B.; Jadhav, A.; Herold, J. M.; Frye, S. V.; Arrowsmith, C. H.; Brown, P. J.; Simeonov, A.; Vedadi, M.; Jin, J.* “Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a” J. Med. Chem. 2009, 52, 7950-7953.
5. Wigle, T. J.; Provencher, L. M.; Norris, J. L.; Jin, J.; Brown, P. J.; Frye, S. V.; Janzen, W. P.* “Accessing Protein Methyltransferase and Demethylase Enzymology Using Microfluidic Capillary Electrophoresis" Chemistry & Biology 2010, 17, 695-704.
6. Siarheyeva, A.; Senisterra, G.; Allali-Hassani, A.; Dong, A.; Dobrovetsky, E.; Wasney, Gregory A.; Chau, I.; Marcellus, R.; Hajian, T.; Liu, F.; Korboukh, I.; Smil, D.; Bolshan, Y.; Min, J.; Wu, H.; Zeng, H.; Loppnau, P.; Poda, G.; Griffin, C.; Aman, A.; Brown, Peter J.; Jin, J.; Al-awar, R.; Arrowsmith, Cheryl H.; Schapira, M.*; Vedadi, M.* "An Allosteric Inhibitor of Protein Arginine Methyltransferase 3" Structure 2012, 20, 1425-1435 (PMID: 22795084).
7. Liu, F.; Li, F.; Ma, A.; Dobrovetsky, E.; Dong, A.; Gao, C.; Korboukh, I.; Liu, J.; Smil, D.; Brown, P. J.; Frye, S. V.; Arrowsmith, C. H.; Schapira, M.; Vedadi, M.*; Jin, J.* “Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors” J. Med. Chem. 2013, 56, 2110-2124.
8. Konze, K. D.; Ma, A.; Li, F.; Barsyte-Lovejoy, D.; Parton, T.; MacNevin, C. J.; Liu, F.; Gao, C.; Huang, X. P.; Kuznetsova, E.; Rougie, M.; Jiang, A.; Pattenden, S. G.; Norris, J. L.; James, L. I.; Roth, B. L.; Brown, P. J.; Frye, S. V.; Arrowsmith, C. H.; Hahn, K. M.; Wang, G. G.; Vedadi, M.; Jin, J.* “An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1”, ACS Chemical Biology, 2013, in press (http://pubs.acs.org/doi/abs/10.1021/cb400133j).

Discovery of Functionally Selective Ligands of GPCRs

GPCRs signal not only via canonical pathways involving heterotrimeric large G proteins, but also via non-canonical G protein-independent interactions with other signaling proteins including, most prominently, beta-arrestins. The process by which GPCR ligands differentially modulate canonical and non-canonical signal transduction pathways is a phenomenon known as “functional selectivity”. Such functionally selective ligands preferentially engage either canonical or non-canonical GPCR pathways. The discovery of ligands with discrete functional selectivity profiles will be extremely useful for elucidating the key signal transduction pathways essential for both the therapeutic actions and side-effects of drugs. However, only a small number of functionally selective GPCR ligands have been reported to date. In addition to the paucity of such ligands, very little purposeful attention has been devoted to creating and annotating novel ligands with distinct patterns of functional selectivity. The Jin lab in collaboration with the Bryan Roth lab at UNC – CH has taken a combined medicinal chemistry and comprehensive pharmacological profiling approach to generating functionally selective GPCR ligands. We have recently discovered the first beta-arrestin-biased agonists of dopamine D₂ receptors.

1. Allen, J. A.; Yost, J. M.; Setola, V.; Chen, X.; Sassano, M. F.; Chen, M.; Peterson, S.; Yadav, P. N.; Huang, X.-P.; Feng, B.; Jensen, N. H.; Che, X.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Caron, M. G.; Javitch, J. A.; Roth, B. L.*; Jin, J.* “Discovery of beta-Arrestin-Biased Dopamine D₂ Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy” Proc Natl Acad Sci U S A, 2011, 108, 18488-18493. (Highlighted by SciBX as a cover story (2011, 4(44), doi:10.1038/scibx.2011.1224), Schizophrenia Research Forum, and Faculty of 1000)
2. Chen, X.; Sassano, M. F.; Zheng, L.; Setola, V.; Chen, M.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Roth, B. L.*; Jin, J.* “Structure-Functional Selectivity Relationship Studies of Beta-arrestin-biased Dopamine D₂ Receptor Agonists” J. Med. Chem. 2012, 55, 7141-7153 (PMID: 22845053).