Discovery of Selective Inhibitors 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 histone methyltransferases (HMTs) has been increasingly recognized as a major signaling mechanism in eukaryotic cells. HMTs are divided into two categories: lysine methyltransferases (PKMTs) and arginine methyltransferases (PRMTs), More than 50 PKMTs and 9 PRMTs have been identified. Mounting evidence suggests that HMTs play crucial roles in various human diseases. To create high quality selective inhibitors of HMTs, the Jin lab has taken a systematic approach by targeting the HMT substrate binding groove, cofactor binding site, and potential allosteric binding site(s). Our recent publications in this area include:

  1. Chen, S.; Wiewiora, R. P.; Meng, F.; Babault, N.; Ma, A.; Yu, W.; Qian, K.; Hu, H.; Zou, H.; Wang, J.; Fan, S.; Blum, G.; Pittella-Silva, F.; Beauchamp, K. A.; Tempel, W.; Jiang, H.; Chen, K.; Skene, R. J.; Zheng, Y. G.; Brown, P. J.; Jin, J.; Luo, C.; Chodera, J. D.; Luo, M. The dynamic conformational landscape of the protein methyltransferase SETD8. eLife 2019, 8, e45403. Just Accepted. PMID : 31081496, PMCID: in progress. DOI:
  2. Veo, B.; Danis, E.; Pierce, A.; Sola, I.; Wang, D.; Foreman, N. K.; Jin, J.; Ma, A.; Serkova, N.; Venkataraman, S.; Vibhakar, R. Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma. JCI Insight 2019, 4(1), e122933. DOI:, PMID: 30626740 PMCID: in progress.
  3. Scheer, S.; Ackloo, S.; Medina, T. S.; Schapira, M.; Li, F.; Ward, J. A.; Lewis, A. M.; Northrop, J. P.; Richardson, P. L.; Kaniskan, H. Ü.; Shen, Y.; Liu, J.; Smil, D.; McLeod, D.; Zepeda-Velazquez, C. A.; Luo, M.; Jin, J.; Barsyte-Lovejoy, D.; Huber, K. V. M.; De Carvalho, D. D.; Vedadi, M.; Zaph, C.; Brown, P. J.; Arrowsmith, C. H.  A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. Nat Commun 2019, 10, 19. DOI:, PMID:30604761, PMCID:PMC6318333.
  4. Zhang, T.; Wu, J.; Ungvijanpunya, N.; Jackson-Weaver, O.; Gou, Y.; Feng, J.; Ho, T. V.; Shen, Y.; Liu, J.; Richard, S.; Jin, J.; Hajishengallis, G.; Chai, Y.; Xu, J.* Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation. Journal of Dental Research 2018, 7, 810-819. PMID: 29420098  PMCID: in progress.
  5. Wang, D.-y.; Kosowan, J.; Samsom, J.; Leung, L.; Zhang, K.-l.; Li, Y.-x.; Xiong, Y.; Jin, J.; Petronis, A.; Oh, G.; Wong, A. H. C.* Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice. Acta Pharmacologica Sinica 2018, 39, 866-874. PMID: 29417943  PMCID: PMC5943902
  6. Kaniskan, H. Ü.; Eram, M. S.; Zhao, K.; Szewczyk, M. M.; Yang, X.; Schmidt, K.; Luo, X.; Xiao, S.; Dai, M.; He, F.; Zang, I.; Lin, Y.; Li, F.; Dobrovetsky, E.; Smil, D.; Min, S.-J.; Lin-Jones, J.; Schapira, M.; Atadja, P.; Li, E.; Barsyte-Lovejoy, D.; Arrowsmith, C. H.; Brown, P. J.; Liu, F.*; Yu, Z.*; Vedadi, M.*; Jin, J.* Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3). Journal of Medicinal Chemistry 2018, 61, 1204-1217. PMID: 29244490  PMCID: PMC5808361
  7. Morini, M. F.; Giampietro, C.; Corada, M.; Pisati, F.; Lavarone, E.; Cunha, S. I.; Conze, L. L.; O’Reilly, N. J.; Joshi, D.; Kjaer, S.; George, R.; Nye, E.; Ma, A.; Jin, J.; Mitter, R.; Lupia, M.; Cavallaro, U.; Pasini, D.; Calado, D. P.; Dejana, E.*; Taddei, A.* VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression. Circulation Research 2018, 122, 231-245. PMID: 29233846  PMCID: PMC5771688
  8. Kaniskan, H. Ü.*; Martini, M. L.; Jin, J.* Inhibitors of Protein Methyltransferases and Demethylases. Chemical Reviews 2018, 118, 989-1068. PMID: 28338320  PMCID: PMC5610952
  9. Alzrigat, M.*; Párraga, A. A.; Majumder, M. M.; Ma, A.; Jin, J.; Österborg, A.; Nahi, H.; Nilsson, K.; Heckman, C. A.; Öberg, F.; Kalushkova A.; Jernberg-Wiklund H.* The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains Oncotarget 20178, 103731–103743. PMID: 2829262596  PMCID: PMC5732762
  10. 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. Bioorganic & Medicinal Chemistry 2017, 25, 4414-4423. PMID: 28662962  PMCID: PMC5562403
  11. Kaniskan, H. Ü.*; Jin, J.* Recent progress in developing selective inhibitors of protein methyltransferases. Current Opinion in Chemical Biology 2017, 39, 100-108. PMID: 28662389  PMCID: PMC5624721
  12. Huang, Q.; He, S.; Tian, Y.; Gu, Y.; Chen, P.; Li, C.; Huang, J.; Liu, Y.; Yu, H.; Jin, M.; Hu, S.; Tong, Q.; Ma, A.; Jin, J.; Hexner, E.; Fung, H.; Reshef, R.; Zhang, Y.*; Zhang, Y.* Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice. Blood 2017, . PMID:28246193  PMCID: PMC5437825
  13. Xiong, Y.; Li, F.; Babault, N.; Dong, A.; Zeng, H.; Wu, H.; Chen, X.; Arrowsmith, C. H.; Brown, P. J.; Liu, J.; Vedadi, M.*; Jin, J.* Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase. J. Med. Chem. 2017, 60, 1876-1891. PMID: 28135087  PMCID: PMC5352984
  14. Veschi, V.; Liu, Z.; Voss, T. C.; Ozbun, L.; Gryder, B.; Yan, C.; Hu, Y.; Ma, A.; Jin, J.; Mazur, S. J.; Lam, N.; Souza, B. K.; Giannini, G.; Hager, G. L.; Arrowsmith, C. H.; Khan, J.; Appella, E.; Thiele, C. J.* Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer Cell 2017, 31, 50-63. PMID: 28073004  PMCID: PMC5233415
  15. Alzrigat, M.*; Párraga, A. A.; Agarwal, P.; Zureigat, H.; Österborg, A.; Nahi, H.; Ma, A.; Jin, J.; Nilsson, K.; Öberg, F.; Kalushkova, A.; Jernberg-Wiklund, H.* EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget 2017, 8, 10213-10224. PMID: 28052011  PMCID: PMC5354653
  16. Kim, Y.; Lee, H.-M.; Xiong, Y.; Sciaky, N.; Hulbert, S. W.; Cao, X.; Everitt, J. I.; Jin, J.; Roth, B. L.*; Jiang, Y.-h.* Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. Nat. Med. 2017, 23, 213-222. PMID: 28024084  PMCID: PMC5589073
  17. Butler, K. V.; Ma, A.; Yu, W.; Li, F.; Tempel, W.; Babault, N.; Pittella-Silva, F.; Shao, J.; Wang, J.; Luo, M.; Vedadi, M.; Brown, P. J.; Arrowsmith, C. H.; Jin, J.* Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. J. Med. Chem. 2016, 59, 9881-9889. PMID: 27804297  PMCID: PMC5148670
  18. Shen, Y.; Szewczyk, M. M.; Eram, M. S.; Smil, D.; Kaniskan, H. Ü.; de Freitas, R. F.; Senisterra, G.; Li, F.; Schapira, M.; Brown, P. J.; Arrowsmith, C. H.; Barsyte-Lovejoy, D.; Liu, J.*; Vedadi, M.*; Jin, J.* Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6. J. Med. Chem. 2016, 59, 9124-9139. PMID: 27584694  PMCID: PMC5063716
  19. Yang, X.; Li, F.; Konze, K. D.; Meslamani, J.; Ma, A.; Brown, P. J.; Zhou, M.-M.; Arrowsmith, C. H.; Kaniskan, H. Ü.; Vedadi, M.*; Jin, J.* Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors. J. Med. Chem. 2016, 59, 7617-7633. PMID: 27468126  PMCID: PMC5003625
  20. Kaniskan, H. U.; Eram, M. S.; Liu, J.; Smil, D.; Martini, M. L.; Shen, Y.; Santhakumar, V.; Brown, P. J.; Arrowsmith, C. H.; Vedadi, M.*; Jin, J.* Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1). MedChemComm 2016, 7, 1793-1796. PMID: 28042453  PMCID: PMC5198778
  21. Agarwal, P.; Alzrigat, M.; Párraga, A. A.; Enroth, S.; Singh, U.; Ungerstedt, J.; Österborg, A.; Brown, P. J.; Ma, A.; Jin, J.; Nilsson, K.; Öberg, F.; Kalushkova, A.*; Jernberg-Wiklund, H*. “Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target” Oncotarget 2016, 7, 6809-6823. PMID:26755663  PMCID: PMC4872750
  22. Eram, M. S.; Shen, Y.; Szewczyk, M.; Wu, H.; Senisterra, G.; Li, F.; Butler, K. V.; Kaniskan, H. Ü.; Speed, B. A.; dela Seña, C.; Dong, A.; Zeng, H.; Schapira, M.; Brown, P. J.; Arrowsmith, C. H.; Barsyte-Lovejoy, D.; Liu, J.*; Vedadi, M.*; Jin, J.* “A Potent, Selective and Cell-active Inhibitor of Human Type I Protein Arginine Methyltransferases” ACS Chemical Biology 2016, 11, 772-781. PMID:26598975  PMCID: PMC4798913
  23. Simon, J. M.; Parker, J. S.; Liu, F.; Rothbart, S. B.; Ait-Si-Ali, S.; Strahl, B. D.; Jin, J.; Davis, I. J.; Mosley, A. L.; Pattenden, S. G.* “A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin” Journal of Biological Chemistry 2015, 290, 26088-26102. PMID: 26338712 PMCID: PMC4646261
  24. Arrowsmith, C. H.; Audia, J. E.; Austin, C.; Baell, J.; Bennett, J.; Blagg, J.; Bountra, C.; Brennan, P. E.; Brown, P. J.; Bunnage, M. E.; Buser-Doepner, C.; Campbell, R. M.; Carter, A. J.; Cohen, P.; Copeland, R. A.; Cravatt, B.; Dahlin, J. L.; Dhanak, D.; Edwards, A. M.; Frye, S. V.; Gray, N.; Grimshaw, C. E.; Hepworth, D.; Howe, T.; Huber, K. V. M.; Jin, J.; Knapp, S.; Kotz, J. D.; Kruger, R. G.; Lowe, D.; Mader, M. M.; Marsden, B.; Mueller-Fahrnow, A.; Muller, S.; O’Hagan, R. C.; Overington, J. P.; Owen, D. R.; Rosenberg, S. H.; Roth, B.; Ross, R.; Schapira, M.; Schreiber, S. L.; Shoichet, B.; Sundstrom, M.; Superti-Furga, G.; Taunton, J.; Toledo-Sherman, L.; Walpole, C.; Walters, M. A.; Willson, T. M.; Workman, P.; Young, R. N.; Zuercher, W. J. “The promise and peril of chemical probes” Nature Chemical Biology 201511, 536-541. PMID: 26196764  PMCID: PMC4706458
  25. Xu, B.; Konze, K. D.; Jin, J.; Wang, G. G.* “Targeting EZH2 and PRC2 dependence as novel anti-cancer therapy” Experimental Hematology 2015, 43, 698-712. PMID: 26027790  PMCID: PMC4706459.
  26. Abou El Hassan, M.; Huang, K.; Eswara, M. B. K.; Zhao, M.; Song, L.; Yu, T.; Liu, Y.; Liu, J. C.; McCurdy, S.; Ma, A.; Wither, J.; Jin, J.; Zacksenhaus, E.; Wrana, J. L.; Bremner, R.* “Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways” PLoS ONE 201510, e0126466. PMID: 26030458 PMCID: PMC4450877
  27. Kaniskan, H. Ü.; Szewczyk, M. M.; Yu, Z.; Eram, M. S.; Yang, X.; Schmidt, K.; Luo, X.; Dai, M.; He, F.; Zang, I.; Lin, Y.; Kennedy, S.; Li, F.; Dobrovetsky, E.; Dong, A.; Smil, D.; Min, S.-J.; Landon, M.; Lin-Jones, J.; Huang, X.-P.; Roth, B. L.; Schapira, M.; Atadja, P.; Barsyte-Lovejoy, D.; Arrowsmith, C. H.; Brown, P. J.; Zhao, K.*; Jin, J.*; Vedadi, M.* “A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)” Angewandte Chemie International Edition 201554, 5166-5170. PMID: 25728001  PMCID: PMC4400258
  28. Kaniskan, H. Ü.; Konze, K.D.; Jin, J.* “Selective Inhibitors of Protein Methyltransferases” J. Med. Chem. 2015, 58, 1596-1629. PMID: 25406853  PMCID: PMC4345896
  29. Kaniskan, H. Ü.; Jin, J.* “Chemical Probes of Histone Lysine Methyltransferases” ACS Chem. Biol. 2015, 10, 40-50. PMID: 25423077  PMCID: PMC4301070
  30. Xu, B.; On, D. M.; Ma, A.; Parton, T.; Konze, K.D.; Pattenden, S. G.; Allison, D.F.; Cai, L.; Rockowitz, S.; Liu, S.; Liu, Y.; Li, F.; Vedadi, M.; Frye, S. V.; Garcia, B. A.; Zheng, D.; Jin, J.; Wang, G. G.* “Selective Inhibition of EZH2 and EZH1 Enzymatic Activity by a Small Molecule Suppresses MLLrearranged Leukemia” Blood, 2015, 125, 346-357. PMID: 25395428  PMCID: PMC4287641
  31. Katona, B., Liu, Y., Ma, A., Jin, J., Hua, X.* “EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells” Cancer Biology & Therapy2014, 15, 1677-1687. PMID: 25535899  PMCID: PMC4622469
  32. Liu, C.; Yu, Y.; Liu, F.; Wei, X.; Wrobel, J. A.; Gunawardena, H. P.; Zhou, L.; Jin, J.; Chen, X.* “A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing” Nature Communications, 2014, 5:5733. PMID: 25502336  PMCID: PMC4360912
  33. Ma, A.; Yu, W.; Xiong, Y.; Butler, K. V.; Brown, P. J.; Jin, J.* “Structure-activity Relationship Studies of SETD8 Inhibitors”  MedChemComm20145, 1892-1898. PMID: 25554733  PMCID: PMC4278651
  34. Ma, A.; Yu, W.; Li, F.; Bleich, R. M.; Herold, J. M.; Butler, K. V.; Norris, J. L.; Korboukh, V.; Tripathy, A.; Janzen, W. P.; Arrowsmith, C. H.; Frye, S. V.; Vedadi, M.; Brown, P. J.; Jin, J.* “Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8” J. Med. Chem. 2014, 57, 6822-6833. PMID: 25032507  PMCID: PMC4136711.
  35. Sundriyal, S.; Malmquist, N. A.; Caron, J.;Blundell, S.; Liu, F.; Chen, X.; Srimongkolpithak, N.; Jin, J.; Charman, S. A.; Scherf, A.; Fuchter, M. J.* “Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds” ChemMedChem, 2014, 9, 2360-2373. PMID: 25044750 PMCID: PMC4177335.
  36. Konze, K. D.; Pattenden, S. G.; Liu, F.; Barsyte-Lovejoy, D.; Li, F.; Simon, J. M.; Davis, I. J.; Vedadi, M.; Jin, J.* “A Chemical Tool for in vitro and in vivo Precipitation of the Lysine Methyltransferase G9a” ChemMedChem, 20149, 549-553. (Cover story) PMID: 24443078  PMCID: PMC4005005
  37. Lehnertz, B.; Pabst, C.; Su, L.; Miller, M.; Liu, F.; Yi, L.; Zhang, R.; Krosl, J.; Yung, E.; Kirschner, J.; Rosten, P.; Underhill, T. M.; Jin, J.; Hébert, J.; Sauvageau, G.; Humphries, R. K.; Rossi, F. M.* “The Methyltransferase G9a Regulates HoxA9-Dependent Transcription in AML” Genes & Development, 2014, 28, 317-327.PMID: 24532712 PMCID: PMC3937511
  38. Liu, F.; Barsyte-Lovejoy, D.; Li, F.; Xiong, Y.; Korboukh, V.; Huang, X. P.; Allali-Hassani, A.; Janzen, W. P.; Roth, B. L.; Frye, S. V.; Arrowsmith, C. H.; Brown, P. J.; Vedadi, M.; Jin, J.* “Discovery of an in vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP” J. Med. Chem. 201356, 8931-8942. PMID: 24102134 PMCID: PMC3880643
  39. 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 Biology20138, 1324-1334. (the most read article since online publication on 4/8/2013) PMID:23614352 PMCID: PMC3773059
  40. 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. 201356, 2110-2124. PMID: 23445220  PMCID: PMC4319713
  41. 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 201220, 1425-1435. PMID: 22795084
  42. 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) PMID: 21743462  PMCID: PMC3184254
  43. 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. PMID: 21780790 PMCID: PMC3171737
  44. 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. PMID: 20614940 PMCID: PMC2920043
  45. 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 201017, 695-704. PMID: 20659682  PMCID: PMC2914686
  46. 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. PMID: 19891491  PMCID: PMC2825141

Discovery of Functionally Selective Ligands of GPCRs

G protein-coupled receptors (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 beta-arrestins. The process by which GPCR ligands differentially modulate canonical and non-canonical signal transduction pathways is a phenomenon known as “functional selectivity” (also knows as signaling bias). Such functionally selective ligands (AKA biased 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.  The Jin lab has been actively engaged in generating functionally selective ligands of GPCRs.

  1. Shen, Y.; McCorvy, J. D.; Martini, M. L.; Rodriguiz, R. M.; Progorelov, V. M.; Ward, K. M.; Wetsel, W. C.; Liu, J.; Roth, B. L.; Jin, J. D2 Dopamine Receptor G protein-biased Partial Agonists Based on Cariprazine. J. Med. Chem. 2019 Just Accepted. PMID & PMCID: in progress. DOI:
  2. Martini, M. L.; Liu, J.; Ray, C.; Yu, X.; Huang, X –P.; Urs, A.; Urs, N. M.; McCorvy, J.; Caron, M. G.; Roth, B. L.; Jin, J. Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists. J. Med. Chem. 2019 Just Accepted. PMID: 30875219, PMCID: in progress. DOI:
  3. Allen, D. C.; Carlson, T. L.; Xiong, Y.; Jin, J.; Grant, K. A.; Cuzon Carlson, V. C.* A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N-oxide hydrochloride salt in rhesus macaques. Journal of Pharmacology and Experimental Therapeutics 2019, 368 (2), 199-207, PMID: 30523062, PMCID:PMC6337003.
  4. McCorvy, J. D.*; Wacker, D.; Wang, S.; Agegnehu, B.; Liu, J.; Lansu, K.; Tribo, A. R.; Olsen, R. H. J.; Che, T.; Jin, J.; Roth, B. L.* Structural determinants of 5-HT2B receptor activation and biased agonism. Nature Structural & Molecular Biology 2018, 25, 787-796. PMID: 30127358  PMCID: PMC6237183
  5. Thompson, K. J.; Khajehali, E.; Bradley, S. J.; Navarrete, J. S.; Huang, X.-P.; Slocum, S.; Jin, J.; Liu, J.; Xiong, Y.; Olsen, R.; DiBerto, J.; Boyt, K. M.; Pina, M. M.; Pati, D.; Molloy, C.; Bundgaard, C.; Sexton, P. M.; Kash, T. L.; Krashes, M. J.; Christopoulos, A.; Roth, B. L.*; Tobin, A. B.* DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo. ACS Pharmacology & Translational Science 2018, 1, 61-72. PMID:30868140, PMCID:PMC6407913
  6. McCorvy, J. D.; Butler, K. V.; Kelly, B.; Rechsteiner, K.; Karpiak, J.; Betz, R. M.; Kormos, B. L.; Shoichet, B. K.; Dror, R. O.*; Jin, J.*; Roth, B. L.* Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nature Chemical Biology 2018, 14, 126-134. PMID: 29227473  PMCID: PMC5771956
  7. Lansu, K.; Karpiak, J.; Liu, J.; Huang, X.-P.; McCorvy, J. D.; Kroeze, W. K.; Che, T.; Nagase, H.; Carroll, F. I.; Jin, J.; Shoichet, B. K.; Roth, B. L. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat. Chem. Biol. 2017, 13, 529-536. PMID: 28288109  PMCID: PMC5391270
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