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. Yu, X.; Li, D.; Kottur, J.; Shen, Y.; Kim, H. S.; Park, K. S.; et al, Kaniskan, H. Ü.; Cai, L.; Jain, R.; Liu, J.; Aggarwal, A. K.; Wang, G. G.*; Jin, J.* A Selective WDR5 Degrader Inhibits Acute Myeloid Leukemia in Patient-Derived Mouse Models. Science Translational Medicine, 2021, 13, eabj1578. PMID: 34586829.
  2. Wei, J.; Meng, F.; Park, K.; Yim, H.; Velez, J.; Kumar, P.; Wang, L.; Xie, L.; Chen, H.; Shen, Y.; Teichman, E.; Wang, G.; Chen, X.; Kaniskan, H.*; Jin, J.* Harnessing the E3 ligase KEAP1 for targeted protein degradation. J. Am. Chem. Soc.  2021, 143, 37, 15073–15083.PMID: 34520194, PMCID: PMC8480205.
  3. Xu, J.;  Yu, X.;  Martin, T. C.;  Bansal, A.; Cheung, K.;  Lubin, A.;  Stratikopoulos, E.;  Cahuzac, K. M.;  Wang, L.; Xie, L.;  Zhou, R.;  Shen, Y.; Wu, X.;  Yao, S.;  Qiao, R.; Poulikakos, P. I.;  Chen, X.;  Liu, J.; Jin, J.*; Parsons, R.* AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild-type KRAS and BRAF by destabilizing Aurora kinase B. Cancer Discovery 2021, PMID: 34301793. DOI: 10.1158/2159-8290.CD-20-0815.
  4. 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:318109273, PMCID: PMC6982609.
  5. Dale, B.; Cheng, M.; Park, K.-S.; Kaniskan, H. Ü.; Xiong, Y.*; Jin, J*. Advancing targeted protein degradation for cancer therapy. Nature Reviews Cancer 2021, 21, 638-654. PMID:34131295, PMCID: PMC8463487.

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.