{"id":38,"date":"2014-10-28T13:55:00","date_gmt":"2014-10-28T17:55:00","guid":{"rendered":"http:\/\/labs.icahn.mssm.edu\/jinlab\/?page_id=38"},"modified":"2024-08-29T17:42:20","modified_gmt":"2024-08-29T17:42:20","slug":"research-2","status":"publish","type":"page","link":"https:\/\/labs.icahn.mssm.edu\/jinlab\/research-2\/","title":{"rendered":"Research"},"content":{"rendered":"

Discovery of Selective Inhibitors for Histone Methyltransferases<\/strong><\/p>\n

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.<\/p>\n

Discovery of Biased Ligands for <\/strong>G Protein-coupled Receptors<\/strong><\/p>\n

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.<\/p>\n

Discovery of Novel Degraders Targeting Oncogenic Proteins<\/strong><\/p>\n

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.<\/p>\n

 <\/p>\n

Selected HMT inhibitor papers:<\/strong><\/p>\n

    \n
  1. Eram, M. S.<\/u>; Shen, Y.<\/u>; Szewczyk, M.<\/u>; Wu, H.; Senisterra, G.; Li, F.; Butler, K. V.; Kaniskan, H. \u00dc.; Speed, B. A.; dela Se\u00f1a, C.; Dong, A.; Zeng, H.; Schapira, M.; Brown, P. J.; Arrowsmith, C. H.; Barsyte-Lovejoy, D.; Liu, J.*; Vedadi, M.*; Jin, J.* \u201cA Potent, Selective and Cell-active Inhibitor of Human Type I Protein Arginine Methyltransferases\u201d ACS Chemical Biology<\/em> 2016<\/strong>, 11<\/em>, 772-781. PMID: 26598975<\/a>, \u00a0PMCID: PMC4798913.<\/li>\n
  2. Kaniskan, H. \u00dc.<\/u>; Szewczyk, M. M.<\/u>; Yu, Z.<\/u>; Eram, M. S.<\/u>; 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.* \u201cA Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)\u201d\u00a0Angewandte Chemie International Edition<\/em> 2015<\/strong>, 54<\/em>, 5166-5170.<\/strong>\u00a0PMID:\u00a025728001,<\/a>\u00a0\u00a0PMCID:\u00a0PMC4400258.<\/li>\n
  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.;\u00a0Jin, J.* \u201cDiscovery of an in vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP\u201d\u00a0J. Med. Chem.\u00a0<\/em>2013<\/strong>,\u00a056<\/em>, 8931-8942.\u00a0PMID:\u00a024102134,<\/a>\u00a0PMCID:\u00a0PMC3880643.<\/li>\n
  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.* \u201cAn Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1\u201d,\u00a0ACS Chemical Biology<\/em>,\u00a02013<\/strong>,\u00a08<\/em>, 1324-1334.\u00a0PMID:\u00a023614352<\/a>, PMCID:\u00a0PMC3773059.<\/li>\n
  5. Vedadi, M.<\/u>; Barsyte-Lovejoy, D.<\/u>; Liu, F.<\/u>; 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.* \u201cA Chemical Probe Selectively Inhibits G9a and GLP Methyltransferase Activity in Cells\u201d Nature Chemical Biology<\/em>, 2011<\/strong>, 7<\/em>, 566-574.\u00a0PMID:\u00a021743462,<\/a>\u00a0PMCID:\u00a0PMC3184254.<\/li>\n<\/ol>\n

    Selected GPCR biased ligand papers:<\/strong><\/p>\n

      \n
    1. Yu, X.<\/u>; Huang, X. -P.; Kenakin, T.; Slocum, S.; Chen, X.; Martini, M.; Liu, J.*; Jin, J.* Design, Synthesis and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68). J. Med. Chem. <\/em> 2019<\/strong>, 62(16), 7557-7574. PMID: 31298539,<\/a> PMCID: PMC6923801.<\/li>\n
    2. Martini, M. L.<\/u>; 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\u00a0<\/em>2019<\/strong>,\u00a010<\/span>, 9<\/span>, 4160-4182.<\/span> PMID: 31387346,<\/a>\u00a0PMCID: PMC6785188.<\/li>\n
    3. McCorvy, J. D.<\/u>; Butler, K. V.<\/u>; Kelly, B.<\/u>; 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 \u03b2-arrestin-biased ligands for aminergic GPCRs. Nature Chemical Biology<\/em> 2018<\/strong>, 14<\/em>, 126-134. PMID: 29227473,<\/a>\u00a0PMCID: PMC5771956.<\/li>\n
    4. 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. <\/em>2016<\/strong>, 59<\/em>, 10601-10618.\u00a0PMID:\u00a027805392<\/a>, PMCID: PMC5148701.<\/li>\n
    5. Chen, X.<\/u>; Sassano, M. F.<\/u>; Zheng, L.; Setola, V.; Chen, M.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Roth, B. L.*; Jin, J.* \u201cStructure-Functional Selectivity Relationship Studies of Beta-arrestin-biased Dopamine D2<\/sub> Receptor Agonists\u201d J. Med. Chem. <\/em>2012,<\/strong> 55<\/em>, 7141-7153.\u00a0PMID: 22845053<\/a>, PMCID:\u00a0PMC3443605.<\/li>\n
    6. Allen, J. A.<\/u>; Yost, J. M.<\/u>; Setola, V.<\/u>; 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.* \u201cDiscovery of Beta-Arrestin-Biased Dopamine D2<\/sub> Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy\u201d PNAS<\/em>, 2011<\/strong>, 108, 18488-18493.\u00a0PMID:\u00a022025698<\/a>, \u00a0PMCID:\u00a0PMC3215024.<\/li>\n<\/ol>\n

      Selected novel degrader papers:<\/strong><\/p>\n

        \n
      1. Yu, X.; Li, D.; Kottur, J.;\u00a0<\/u>Shen, Y.; Kim, H. S.; Park, K. S.; et al, Kaniskan, H. \u00dc.; Cai, L.; Jain, R.; Liu, J.; Aggarwal, A. K.; Wang, G. G.*;\u00a0Jin, J.*\u00a0A Selective WDR5 Degrader Inhibits Acute Myeloid Leukemia in Patient-Derived Mouse Models.\u00a0Science Translational Medicine<\/em><\/strong>, 2021, 13, eabj1578. PMID: 34586829<\/a>.<\/li>\n
      2. Wei, J.; Meng, F.;\u00a0<\/u>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.\u00a0J. Am. Chem. Soc.<\/em><\/strong>\u00a0\u00a02021, 143, 37, 15073\u201315083.PMID: 34520194<\/a>, PMCID: PMC8480205.<\/li>\n
      3. Xu, J.;\u00a0 Yu, X.;<\/u>\u00a0\u00a0Martin, T. C.;\u00a0 Bansal, A.;\u00a0Cheung, K.;\u00a0 Lubin, A.;\u00a0 Stratikopoulos, E.;\u00a0 Cahuzac, K. M.;\u00a0 Wang, L.;\u00a0Xie, L.;\u00a0 Zhou, R.;\u00a0 Shen, Y.;\u00a0Wu, X.;\u00a0 Yao, S.;\u00a0 Qiao, R.;\u00a0Poulikakos, P. I.;\u00a0 Chen, X.;\u00a0 Liu, J.;\u00a0Jin, 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.\u00a0Cancer Discovery\u00a0<\/em><\/strong>2021, PMID:\u00a034301793<\/a>. DOI:\u00a010.1158\/2159-8290.CD-20-0815.<\/li>\n
      4. Ma, A.;\u00a0Stratikopoulos, E.;\u00a0Park, K \u2013S.;\u00a0<\/u>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.\u00a0Nature Chemical Biology<\/em><\/strong>\u00a02020,16,\u00a0214\u2013222. PMID:318109273<\/a>, PMCID: PMC6982609.<\/li>\n
      5. Dale, B.; Cheng, M.;\u00a0<\/u>Park, K.-S.; Kaniskan, H. \u00dc.; Xiong, Y.*; Jin, J*. Advancing targeted protein degradation for cancer therapy.\u00a0Nature Reviews Cancer<\/em><\/strong>\u00a0<\/em>2021, 21, 638-654.\u00a0PMID:34131295<\/a>, PMCID:\u00a0PMC8463487.<\/li>\n<\/ol>\n

        Reviews: <\/strong><\/p>\n

          \n
        1. Dale, B.; Cheng, M.;\u00a0Park, K.-S.; Kaniskan, H. \u00dc.; Xiong, Y.*; Jin, J*. Advancing targeted protein degradation for cancer therapy.\u00a0Nature Reviews Cancer\u00a0<\/strong><\/em>, 2021<\/em>, 21, 638-654. PMID: 34131295,<\/a> PMCID:\u00a0PMC8463487<\/li>\n
        2. Kaniskan, H. \u00dc.*; Martini, M. L.; Jin, J.* Inhibitors of Protein Methyltransferases and Demethylases.\u00a0Chemical Reviews\u00a0<\/strong><\/em>2018,\u00a0118, 989-1068.\u00a0PMID:\u00a028338320,<\/a> PMCID: PMCID: 28338320.<\/li>\n
        3. Bhat, K. P.;\u00a0\u00a0\u00dcmit Kaniskan, H.;\u00a0 Jin, J.*; Gozani, O.* Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.\u00a0Nature Reviews Drug Discovery<\/strong><\/em>\u00a02021<\/em>,\u00a020, 265-286. PMID: 33469207,<\/a> PMCID: PMC8035146.<\/li>\n
        4. Kabir, M.; Yu, X.; Kaniskan, H. \u00dc.*; Jin, J.*; Chemically induced degradation of epigenetic targets.\u00a0Chemical Society Reviews,\u00a02023<\/em>, 52(13):4313-4342.\u00a0PMID:37314393.<\/a><\/li>\n
        5. Kaniskan, H. \u00dc.; Jin, J.* \u201cChemical Probes of Histone Lysine Methyltransferases\u201d\u00a0ACS Chemical Biology<\/em><\/strong> \u00a02015,\u00a010, 40-50.\u00a0PMID:25423077\u00a025423077, <\/a>PMCID:4301070<\/li>\n
        6. Kaniskan, H. \u00dc.; Konze, K.D.; Jin, J.* \u201cSelective Inhibitors of Protein Methyltransferases\u201d\u00a0Journal of Medicinal Chemistry<\/em>\u00a0<\/strong>2015,\u00a058,\u00a01596-1629.\u00a0PMID:25406853,\u00a0<\/a>\u00a0PMCID: PMCID4345896<\/li>\n<\/ol>\n

          Other selected papers:<\/strong><\/p>\n

            \n
          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.<\/em> 2020<\/strong>, 38, 50\u201355. PMID: 31712774<\/a>, PMCID: PMC6954327.<\/li>\n
          2. Butler, K. V.; Chiarella, A. M.<\/u>; Jin, J. *; Hathaway N. A.* Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity.\u00a0ACS Synth. Biol.<\/em> 2018<\/strong>, 7, 38-45. PMID: 29073761<\/a>, PMCID: PMC5775041.<\/li>\n
          3. Chen, X.; Choo, H.<\/u>; 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<\/em> 2015<\/strong>, 6, 476-484. PMID: 25587888<\/a>, PMCID: PMC4368042.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

            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 […]<\/p>\n","protected":false},"author":43,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"open","ping_status":"open","template":"","meta":{"footnotes":""},"class_list":["post-38","page","type-page","status-publish","hentry"],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/pages\/38","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/users\/43"}],"replies":[{"embeddable":true,"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/comments?post=38"}],"version-history":[{"count":151,"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/pages\/38\/revisions"}],"predecessor-version":[{"id":1548,"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/pages\/38\/revisions\/1548"}],"wp:attachment":[{"href":"https:\/\/labs.icahn.mssm.edu\/jinlab\/wp-json\/wp\/v2\/media?parent=38"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}