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Jian Jin

  • SENIOR FACULTY Structural and Chemical Biology
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Education

  • B.S., University of Science and Technology of China
    Chemistry

  • Postdoc, Ohio State University
    Organic Chemistry

  • Ph.D., Pennsylvania State University
    Organic Chemistry

Biography

    Dr. Jian Jin received a B.S. degree in chemistry from University of Science and Technology of China in 1991 and a Ph.D. degree in synthetic organic chemistry from the Pennsylvania State University in 1997, and completed postdoctoral training at the Ohio State University. Dr. Jin joined GlaxoSmithKline as a medicinal chemist in 1998 and had been a manager of medicinal chemistry from 2003 to 2008. In 2008, Dr. Jin joined the Division of Chemical Biology and Medicinal Chemistry at the University of North Carolina at Chapel Hill as a faculty member and served as an associate director of medicinal chemistry in the Center for Integrative Chemical Biology and Drug Discovery. In 2014, Dr. Jin joined the Icahn School of Medicine at Mount Sinai as a Professor of Structural and Chemical Biology, Oncological Sciences, and Pharmacology. Over the last six years, Dr. Jin’s laboratory has focused on discovering chemical probes of protein methyltransferases and functionally selective ligands of G protein-coupled receptors. To date, Dr. Jin has published 87 peer-reviewed papers (including 65 papers since 2008) and delivered more than 50 invited talks. He is also an inventor of 9 issued U.S. patents and 37 published PCT patent applications.

    Lab website: http://labs.icahn.mssm.edu/jinlab/

Research

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.

Discovery of Chemical Probes for Histone Methyltransferases

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 chemical probes 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).

Publications

Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, Allison DF, Cai L, Rockowitz S, Liu S, Liu Y, Li F, Vedadi M, Frye SV, Garcia BA, Zheng D, Jin J, Wang GG. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 2014 Nov;.

Ma A, Yu W, Xiong Y, Butler KV, Brown PJ, Jin J. Structure-activity Relationship Studies of SETD8 Inhibitors. MedChemComm 2014;: DOI: 10.1039/C4MD00317A.

Ma A, Yu W, Li F, Bleich RM, Herold JM, Butler KV, Norris JL, Korboukh V, Tripathy A, Janzen WP, Arrowsmith CH, Frye SV, Vedadi M, Brown PJ, Jin J. Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. Journal of medicinal chemistry 2014 Aug; 57(15).

Sundriyal S, Malmquist NA, Caron J, Blundell S, Liu F, Chen X, Srimongkolpithak N, Jin J, Charman SA, Scherf A, Fuchter MJ. Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds. ChemMedChem 2014 Oct; 9(10).

Wright BD, Loo L, Street SE, Ma A, Taylor-Blake B, Stashko MA, Jin J, Janzen WP, Frye SV, Zylka MJ. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 2014 May; 82(4).

Konze KD, Pattenden SG, Liu F, Barsyte-Lovejoy D, Li F, Simon JM, Davis IJ, Vedadi M, Jin J. A chemical tool for in vitro and in vivo precipitation of lysine methyltransferase G9a. ChemMedChem 2014 Mar; 9(3).

Lehnertz B, Pabst C, Su L, Miller M, Liu F, Yi L, Zhang R, Krosl J, Yung E, Kirschner J, Rosten P, Underhill TM, Jin J, Hébert J, Sauvageau G, Humphries RK, Rossi FM. The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes & development 2014 Feb; 28(4).

Zhou B, Damrauer JS, Bailey ST, Hadzic T, Jeong Y, Clark K, Fan C, Murphy L, Lee CY, Troester MA, Miller CR, Jin J, Darr D, Perou CM, Levine RL, Diehn M, Kim WY. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. The Journal of clinical investigation 2014 Feb; 124(2).

Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. Journal of medicinal chemistry 2013 Nov; 56(21).

Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP, Kuznetsova E, Rougie M, Jiang A, Pattenden SG, Norris JL, James LI, Roth BL, Brown PJ, Frye SV, Arrowsmith CH, Hahn KM, Wang GG, Vedadi M, Jin J. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS chemical biology 2013; 8(6).

Liu F, Li F, Ma A, Dobrovetsky E, Dong A, Gao C, Korboukh I, Liu J, Smil D, Brown PJ, Frye SV, Arrowsmith CH, Schapira M, Vedadi M, Jin J. Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. Journal of medicinal chemistry 2013 Mar; 56(5).

James LI, Barsyte-Lovejoy D, Zhong N, Krichevsky L, Korboukh VK, Herold JM, MacNevin CJ, Norris JL, Sagum CA, Tempel W, Marcon E, Guo H, Gao C, Huang XP, Duan S, Emili A, Greenblatt JF, Kireev DB, Jin J, Janzen WP, Brown PJ, Bedford MT, Arrowsmith CH, Frye SV. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nature chemical biology 2013 Mar; 9(3).

Chen X, Sassano MF, Zheng L, Setola V, Chen M, Bai X, Frye SV, Wetsel WC, Roth BL, Jin J. Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists. Journal of medicinal chemistry 2012 Aug; 55(16).

Korboukh I, Hull-Ryde EA, Rittiner JE, Randhawa AS, Coleman J, Fitzpatrick BJ, Setola V, Janzen WP, Frye SV, Zylka MJ, Jin J. Orally active adenosine A(1) receptor agonists with antinociceptive effects in mice. Journal of medicinal chemistry 2012 Jul; 55(14).

Siarheyeva A, Senisterra G, Allali-Hassani A, Dong A, Dobrovetsky E, Wasney GA, 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 PJ, Jin J, Al-Awar R, Arrowsmith CH, Schapira M, Vedadi M. An allosteric inhibitor of protein arginine methyltransferase 3. Structure (London, England : 1993) 2012 Aug; 20(8).

Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, Johnson NL, Granger DA, Jordan NV, Darr DB, Usary J, Kuan PF, Smalley DM, Major B, He X, Hoadley KA, Zhou B, Sharpless NE, Perou CM, Kim WY, Gomez SM, Chen X, Jin J, Frye SV, Earp HS, Graves LM, Johnson GL. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 2012 Apr; 149(2).

Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton JW, Lee HM, Chen X, Jin J, Bridges AS, Zylka MJ, Roth BL, Philpot BD. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 2012 Jan; 481(7380).

Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J. Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proceedings of the National Academy of Sciences of the United States of America 2011 Nov; 108(45).

Liu F, Barsyte-Lovejoy D, Allali-Hassani A, He Y, Herold JM, Chen X, Yates CM, Frye SV, Brown PJ, Huang J, Vedadi M, Arrowsmith CH, Jin J. Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. Journal of medicinal chemistry 2011 Sep; 54(17).

Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nature chemical biology 2011 Aug; 7(8).

Liu F, Chen X, Allali-Hassani A, Quinn AM, Wigle TJ, Wasney GA, Dong A, Senisterra G, Chau I, Siarheyeva A, Norris JL, Kireev DB, Jadhav A, Herold JM, Janzen WP, Arrowsmith CH, Frye SV, Brown PJ, Simeonov A, Vedadi M, Jin J. Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. Journal of medicinal chemistry 2010 Aug; 53(15).

Johnson SM, Torrice CD, Bell JF, Monahan KB, Jiang Q, Wang Y, Ramsey MR, Jin J, Wong KK, Su L, Zhou D, Sharpless NE. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. The Journal of clinical investigation 2010 Jul; 120(7).

Liu F, Chen X, Allali-Hassani A, Quinn AM, Wasney GA, Dong A, Barsyte D, Kozieradzki I, Senisterra G, Chau I, Siarheyeva A, Kireev DB, Jadhav A, Herold JM, Frye SV, Arrowsmith CH, Brown PJ, 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. Journal of medicinal chemistry 2009 Dec; 52(24).

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. Jin did not report having any of the following types of financial relationships with industry during 2013 and/or 2014: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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