报告题目:Discovery of Chemical Probes for Methyl Writers of the Histone Code

报告人:刘峰博士(Center for Integrative Chemical Biology & Drug Discovery，University of North Carolina at Chapel Hill)

报告时间: 2012年3月16日上午9点30分

报告地点: 独墅湖2期云轩楼1319室

报告摘要: 自从第一个组蛋白甲基化转移酶（HMT）于2000年得到表征以来，随后有超过50种人类 HMT得到了表征， G9a作为其中的一员和许多人类疾病有关，如肿瘤、神经发育迟缓、炎症、毒品成瘾及艾滋病等等；因此研发高活性高选择性的G9a抑制剂，不仅能帮助科学家们深入了解该酶在生物体内所扮演的化学生物学角色，而且在这些抑制剂的研究基础上很可能开发出全新的临床诊断手段或治疗新药。以人类甲基化转移酶G9a为靶点，我们对喹唑啉类分子在合成设计、构效关系上做了详尽的分析和研究，并研发出了第一个高活性高选择性的以G9a为靶点的in vitro有机小分子探针UNC0638；通过对药动和药代结果的分析，随后设计和合成出in vivo有机小分子探针UNC0642.

王建华简介：

厦门大学化学系 (1999年)

中科院上海有机化学研究所博士(2003-2009年)

Advisor: Professor Chao-zhong Li

Dissertation: Research on the Regioselectivities of Primary Aminyl Radical Cyclizations and a Facile Synthesis of 14-Aza Camptothecins.

University of North Carolina 博士后研究（2009至今）。

Advisor: Professor Jian Jin

代表出版物：

1. Zhan, Z*.; Lang, K.; Liu, F.; Hu, L. “Water Effects on SmI2 Reductions: A Novel Method for the Synthesis of Alkyl Thiols by SmI2-Promoted Reductions of Sodium Alkyl Thiosulfates and Alkyl Thiocyanates”. Syn. Commun. 2004, 34, 3203.

2. Liu, F.; Liu, K.; Yuan, X.; Li. C*. “5-Exo versus 6-Endo Cyclization of Primary Aminyl Radicals: An Experimental and Theoretical Investigation”. J. Org. Chem. 2007, 72, 10231.

3. Liu, F.; Li. C*. “Intramolecular Formal [4 + 2] Cycloaddition of Nitriles with Amides Triggered by TMSOTf/Et3N: Highly Efficient Construction of Pyrrolo[1,2-a]pyrimidin-4(6H)-ones”. J. Org. Chem. 2009, 74, 5699.

4. Ju, Y.; Liu, F.; Li. C*. “Palladium-Catalyzed Sequential Cyanation/N-Addition/ N-Arylation in One-Pot: Efficient Synthesis of Luotonin A and Its Derivatives”. Org. Lett. 2009, 11, 3582.

5. 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.

6. 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.

7. Liu, F.; Chen, X.; Allali-Hassani, A.; Quinn, A. M.; Wigle, T. J.; Barsyte, D.; Yost, J. M.; Wasney, G. A.; Dong, A.; Ivona, K.; Senisterra, G.; Chau, I.; Siarheyeva, A.; Van Deusen, 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.* “ Discovery of chemical probes for protein lysine methyltrasferase G9a”. 240th ACS National Meeting, Boston, MA, United States, August 22-26, 2010 (2010).

8. 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 Chem. Biol. 2011, 7, 566. (The first three authors labeled with “#” contributed equally to this paper. Featured by News and Views in Nature Chemical Biology 2011, 7, 499-500)

9. Yost, J. M.; Korboukh, I.; Liu, F.; Gao, C.; Jin, J. * “Targets in Epigenetics: Inhibiting the Methyl Writers of the Histone Code”. Curr. Chem. Genomics 2011, 5, 72. (The first four authors contributed equally to this review.)

10. 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.; Arrowsmith, C. H.; Jin, J.* “Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines”. J. Med. Chem. 2011, 54, 6139.

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