Discovery of Selective Inhibitors for Histone Methyltransferases

Histone methyltransferases (HMTs, also known as protein methyltransferases (PMTs)) play critical roles in various human diseases including cancer. The Jin lab has taken a systematic approach to target HMTs for over a decade. By targeting the HMT substrate binding groove, cofactor binding site, and allosteric binding sites, the Jin lab has discovered numerous high quality selective inhibitors of HMTs, which have been widely used by the scientific community.

Discovery of Biased Ligands for G Protein-coupled Receptors

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. Biased ligands of GPCRs preferentially engage either canonical or non-canonical signaling pathways and are extremely useful tools for elucidating the signal transduction pathways essential for both therapeutic actions and side-effects. The Jin lab has been actively engaged in discovering biased ligands of GPCRs for more than a decade.

Discovery of Novel Degraders Targeting Oncogenic Proteins

The Jin lab is a leader in developing novel degraders targeting oncogenic proteins. Since 2014, the lab has discovered a number of first-in-class degraders using the PROTAC (proteolysis targeting chimera) and hydrophobic tagging technologies. Our degrader program has resulted in multiple patent applications filed by Mount Sinai.


Selected HMT inhibitor papers:

  1. 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.
  2. 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 2015, 54, 5166-5170. PMID: 25728001,  PMCID: PMC4400258.
  3. 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.
  4. 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. PMID: 23614352, PMCID: PMC3773059.
  5. 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. PMID: 21743462, PMCID: PMC3184254.

Selected GPCR biased ligand papers:

  1. Martini, M. L.; Ray, C.; Yu, X.; Liu, J.; Pogorelov, V.; Wetsel, W. C.; Huang, X. P.; McCorvy, J.*; Caron, M. G.*; Jin, J.* Designing Functionally Selective Non-Catechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci 201910, 9, 4160-4182. PMID: 31387346, PMCID: PMC6785188.
  2. 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.
  3. Chen, X.; McCorvy, J. D.; Fischer, M. G.; Butler, K. V.; Shen, Y.; Roth, B. L.*; Jin, J.* Discovery of G Protein-biased D2 Dopamine Receptor Partial Agonists. J. Med. Chem. 2016, 59, 10601-10618. PMID: 27805392, PMCID: PMC5148701.
  4. 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, PMCID: PMC3443605.
  5. 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” PNAS, 2011, 108, 18488-18493. PMID: 22025698,  PMCID: PMC3215024.

Selected novel degrader papers:

  1. Liu, J.; Chen, H.; Ma, L.; He, Z.; Wang, D.; Liu, Y.; Lin, Q.; Zhang, T.; Gray, N.; Kaniskan, H. U.; Jin, J.*; Wei, W.*Light-induced control of protein destruction by opto-PROTAC. Sci. Adv., 2020, 6, eaay5154. PMID: 32128407, PMCID: PMC7034987.
  2. Cheng, M.; Yu, X.*; Lu, K.; Xie, L.; Wang, L.; Meng, F.; Han, X.; Chen, X.; Liu, J.; Xiong, Y.*; Jin, J.* Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-molecule Degraders. J. Med. Chem. 2020, PMID: 31895569, PMCID: In progress.
  3. Ma, A.; Stratikopoulos, E.; Park, K –S.; Wei, J.; Martin, T. C.; Yang, X.; Schwarz, M.; Leshchenko, V.; Rialdi, A.; Dale, B.; Lagana, A.; Guccione, E.; Parekh, S.; Parsons, R.* and Jin, J.* Discovery of a first-in-class EZH2 selective degrader. Nature Chemical Biology 2020,16, 214–222.PMID: 31730343, PMCID: PMC6982609.
  4. Wei, J.; Hu, J.; Wang, L.; Xie, L.; Jin, M. S.; Chen, X.; Liu, J.* and Jin, J.* Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader. J. Med. Chem. 2019. PMID: 31712774, PMCID: In progress.
  5. Zhang, C.; Han, X.-R.; Yang, X.; Jiang, B.; Liu, J.*; Xiong, Y.*; Jin, J.* Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). European Journal of Medicinal Chemistry 2018, 151, 304-314. PMID: 29627725,  PMCID: PMC5924614.

Other selected papers:

  1. Chiarella, A. M.; Butler, K. V.; Gryder, B. E.; Lu, D.; Wang, T. A.; Yu, X.; Pomella, S.; Khan, J.; Jin, J.*; Hathaway, N. A.* Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery. Nature Biotechnology. 2020, 38, 50–55. PMID: 31712774, PMCID: PMC6954327.
  2. Butler, K. V.; Chiarella, A. M.; Jin, J. *; Hathaway N. A.* Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity. ACS Synth. Biol. 2018, 7, 38-45. PMID: 29073761, PMCID: PMC5775041.
  3. Chen, X.; Choo, H.; Huang, X.-P.; Yang, X.; Stone, O.; Roth, B. L.*; Jin, J.* The First Structure-activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). ACS Chemical Neuroscience 2015, 6, 476-484. PMID: 25587888, PMCID: PMC4368042.