药明康德发表论文

谢欣，中科院上海药物研究所研究员，国家新药筛选中心副主任，同济大学生命科学与技术学院 *** 教授。1996年毕业于北京大学化学系，获理学学士学位。2002年获得美国新泽西医科和牙科大学神经科学专业的博士学位。随后转入新泽西医学院从事神经生物学方面的博士后研究工作，期间致力于神经节苷酯对神经细胞内钙离子平衡调控作用的研究。2004年加入国家新药筛选中心担任模型建立II部主管，从事G蛋白偶联受体的信号转导通路研究、小分子化合物对干细胞命运调控的研究及高通量/高内涵新药筛选模型建立及套用工作。她的工作不仅获得中科院"百人计画"择优支持，同时还获得教育部、人事部优秀人才计画，上海市"浦江人才"计画，国家自然科学基金委项目的支持，并于2009年起担任科技部重大科学研究首席科学家。她还获得多项荣誉及奖励，包括"新世纪百千万人才工程国家级人选"，"中科院上海分院系统杰出青年科技创新人才"，"上海市优秀学术带头人"，"上海市三八红旗手"，"国务院 *** 特殊津贴专家"等，并于2013年获第十届"全国优秀青年女科学家"奖。

2005.12-至今, 中国科学院上海药物研究所，研究员，课题组长

2004.05-至今, 国家新药筛选中心，历任模型建立II部主管, 副主任

2003.07-2004.05, 信谊药厂药物研究所，对外合作部主任

2002.05-2003.06, 美国新泽西医科和牙科大学神经科学系，博士后

谢欣课题组主要从事基于G蛋白偶联受体(GPCR)的重大疾病新机制、药物作用新靶点及生物活性新分子研究;近期也利用小分子化合物研究干细胞命运的转变。近年来，谢欣课题组发现两个GPCR(CysLT1和A2B)是治疗自身免疫性疾病多发性硬化症(MS)的潜在药靶，揭示数个老药可有效控制MS，并提出多靶向药物是治疗这类复杂疾病的新思路。还发现老药锂盐和高渗环境均可极大提高多能干细胞诱导效率，为其在药物研发领域的套用提出新概念新方法。谢欣博士及其团队近五年发表通讯作者SCI论文28篇，其中包括IF>10的有3篇，10>IF>3有14篇。全部论文近五年被他引>550次。申请专利34项，获授权13项。目前有两个基于GPCR的新药候选化合物进入系统临床前研究。

1. 自然科学基金, p38活化增强iPS诱导效率的机制研究, 项目负责人, 2014.01-2017.12

2. 中国科学院战略性先导科技专项, 干细胞调控药物的筛选和成药性研究, 课题负责人, 2011.01-2015.12

3. 上海市科委优秀学术带头人, G蛋白偶联受体在自身免疫病中的关键作用研究, 项目负责人, 2012.07-2014.06

4. 上海市科委研发公共服务平台, 新药筛选技术平台的完善与服务能力建设, 项目负责人, 2011.12-2013.09

5. 科技部发育与生殖重大专项, 发育与生殖相关的小分子化合物库及相关技术平台的建立,首席科学家, 2009.01-2013.08

2008.12-至今, ActaPharmacologicaSinica编委

2012.07-至今, the Journal of Biological Chemistry 编委

2014.05-至今, 中国细胞生物学学会干细胞生物学分会，委员

·第十届中国青年女科学家奖(2013年)

·享受国务院 *** 特殊津贴专家(2012年)

· 上海市三八红旗手(2011-2012年)

· 第六届上海青年科技英才提名奖(2012年)

· 第六届药明康德生命化学学者奖(2012年)

· 中科院上海分院系统杰出青年科技创新人才(2012年)

· 新世纪百千万人才工程国家级人选(2009年)

(2009.1.1至今

1) Guofang Chen, Xinxiu Xu, Lihong Zhang, Yanbin Fu, Min Wang, Haifeng Gu, Xin Xie*. Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cells self-renewal and somatic cell reprogramming. Cell Research, 2014, Aepted.

2) Xiaoyuan Wei, Yueting Chen, Yongyu Xu, Yang Zan, Ru Zhang, Min Wang, Qiuhong Hua, Haifeng Gu, Fajun Nan*, Xin Xie*. Small molecule pound induces chromatin de-condensation and facilitate induced pluripotent stem cell generation. Journal of Molecular Cell Biology, 2014 May 15. pii: mju024. [Epub ahead of print]

3) Chenli Ye, Zhenghong Zhang, Zhilong Wang, Qiuhong Hua, Ru Zhang*, and Xin Xie*. Identification of a novel *** all molecule agonist for human GPR3. Journal of Pharmacology and Experimental Therapeutics.2014 Jun;349(3):437-43.

4) Yongyu Xu, Xiaoyuan Wei, Min Wang, Ru Zhang*, Yanbin Fu, Mingzhe Xing, Qiuhong Hua, Xin Xie*. Proliferation rate of somatic cells affects reprogramming efficiency. Journal of Biological Chemistry. 2013, Apr 5;288(14):9767-78.

5) Feifei Zhang, Wei Wei, Hui Chai, Xin Xie*. Aurintricarboxylic Acid Ameliorates Experimental Autoimmune Encephalomyelitis by Blocking Chemokine-mediated Pathogenic Cell Migration and Infiltration. Journal of Immunology. 2013 Feb 1;190(3):1017-25.

6) Wei Wei, Changsheng Du, Jie Lv, Guixian Zhao, Zhenxin Li, Zhiying Wu, György Haskó, Xin Xie*. Blocking A2B Adenosine Receptor alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and TH-17 Differentiation. Journal of Immunology. 2013 Jan 1;190(1):138-46.

7) Xinxiu Xu, Quan Wang, Yuan Long, Ru Zhang, Xiaoyuan Wei, Mingzhe Xing, Haifeng Gu, Xin Xie*. Stress-mediated p38 activation promotes somatic cell reprogramming. Cell Research. 2013 Jan;23(1):131-41.

8) Jie Lv, Changsheng Du, Wei Wei, Zhiying Wu, Guixian Zhao, Zhenxin Li, Xin Xie*. The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis. Journal of Biological Chemistry.2012 Aug 17; 287(34):28656-65.

9) Chang-Sheng Du, Xin Xie*. G Protein-Coupled Receptors as Therapeutic Targets for Multiple Sclerosis. Cell Research. 2012 Jul; 22(7):1108-28.

10) Liefeng Wang, Changsheng Du, Jie Lv, Wei Wei, Ye Cui, Xin Xie*. Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis. Journal of Immunology. 2011;187(5):2336-45.

11) Quan Wang, Xinxiu Xu, Jun Li, Jing Liu, Haifeng Gu, Ru Zhang, Jiekai Chen, Yin Kuang, Jian Fei, Cong Jiang, Ping Wang, Duanqing Pei, Sheng Ding, Xin Xie*. Lithium, an anti-Psychotic Drug, Greatly Enhances the Generation of Induced Pluripotent Stem Cells. Cell Research. 2011;21(10):1424-35.

12) Chenlei Yin, Ru Zhang, Yongyu Xu, Qiuyan Chen, Xin Xie*. Intact Mdm2 E3 Ligase Activity Is Required for the Cytosolic Localization and Function of β-Arrestin2. Molecular Biology of the Cell. 2011 Mar 9; 22(9):1608-16.

研究方向:

基于G蛋白偶联受体的创新药物发现及研究:

G蛋白偶联受体家族(G-Protein-Coupled Receptor, GPCR)是人体内最大的膜受体蛋白家族。目前已知有近一千个基因编码GPCR。GPCR都具有典型的七次跨膜结构，对多种细胞外 *** 如光、气味、离子、神经递质、趋化因子、脂类、肽类和激素等产生反应，介导多种重要的生理功能。GPCR在信号转导通路的源头位置及其介导的生理功能的多样性使其成为最具开发潜力的药物作用靶点，目前市场上有约40%的药物是直接或间接作用与GPCR的。

我们选择这一重要的药物作用靶点家族，开展以下几方面的工作:

1. G蛋白偶联受体高通量/高内涵筛选模型的建立。我们将选择与重大疾病相关的GPCR(如与肥胖症密切相关的大麻受体CB1和黑色素皮质素受体MC4;与爱滋病相关的趋化因子受体CCR5和CXCR4以及与神经系统疾病相关的受体等)，套用分子及细胞生物学知识及实验技巧构建稳定表达受体的细胞系，通过受配体竞争结合、GTPS结合、报告基因检测、胞内cAMP检测、钙流检测、受 *** 移、受体下游信号蛋白位移等方法建立高通量/高内涵筛选模型。

2. 基于重大疾病相关的G蛋白偶联受体靶点的新药筛选。我们将套用上述高通量/高内涵筛选模型对合成或天然来源的化合物进行筛选、验证，以期发现新型小分子药物先导化合物，为进一步结构改造和最佳化打下基础。

3. G蛋白偶联受体信号转导通路研究。传统GPCR 信号转导研究集中在G蛋白亚型与第二信使激活等方面。近期研究发现GPCR还可以和多种膜蛋白及下游信号蛋白直接作用。另我们也发现活性小分子化合物与天然配体的活化作用之间存在一定差异，这可能与受配体间结合部位差异而导致不同的下游信号转导有关。我们希望利用已有的活性小分子化合物为探针，利用化学生物学方法对G蛋白偶联受体信号转导通路进行进一步研究。

已在国外期刊上发表SCI论文近40篇，多篇论文发表在Nature Chemical Biology, Chemistry Biology, J. Med. Chem., J. Org. Chem., Bioconjugate Chem., Chem. Comm., Chem.-Eur. J., Bioorg. Med. Chem. Lett.等国际著名期刊上。1) Thiophene-Core Estrogen Receptor Ligands Having Superagonist Activity. Jian Min, Pengcheng Wang, Sathish Srinivasan, Jerome C. Nwachukwu, Pu Guo, Minjian Huang, Kathryn E. Carlson, John A. Katzenellenbogen*, Kendall W. Nettles, Hai-Bing Zhou*. J. Med. Chem., 2013, 56 (8), 3346–3366. (IF: 5.614)2) Design, Synthesis and Biological Evaluation of Novel Estrogen-derived Steroidal Metal Complexes. Xinlong Zhang, Ziqing Zuo, Juan Tang, Kai Wang, Caihua Wang, Weiyan Chen, Changhao Li, Wen Xu, Xiaolin Xiong, Kangxiang Yuntai, Jian Huang, Xiaoli Lan, Hai-Bing Zhou*. Bioorg. Med. Chem. Lett. 2013, 23 (13), 3793-3797. (IF: 2.338)3) Identification and Structure-Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide. Pengcheng Wang, Jian Min, Jerome C. Nwachukwu, Valerie Cavett, Kathryn E. Carlson, Pu Guo, Manghong Zhu, Yangfan Zheng, Chune Dong, John A. Katzenellenbogen*, Kendall W. Nettles, Hai-Bing Zhou*. J. Med. Chem. 2012, 55 (5), 2324-2341. (IF: 5.614)4) Discovery of novel SERMs with a ferrocenyl entity based on the oxabicyclo[2.2.1]heptene scaffold and evaluation of their antiproliferative effects in breast cancer cells. Yangfan Zheng, Caihua Wang, Changhao Li, Jinxia Qiao, Feng Zhang, Minjian Huang, Wenming Ren, Chune Dong, Jian Huang*, Hai-Bing Zhou*. Org. Biomol. Chem., 2012, 10 (48), 9689-9699. (IF: 3.568)5) Development of Selective Estrogen Receptor Modulator (SERM)-Like Activity Through an Indirect Mechanism of Estrogen Receptor Antagonism: Defining the Binding Mode of 7-Oxabicyclo[2.2.1]hept-5-ene Scaffold Core Ligands. Yangfan Zheng, Manghong Zhu, Sathish Srinivasan, Jerome C. Nwachukwu, Valerie Cavett, Jian Min, Kathryn E. Carlson, Pengcheng Wang, Chune Dong, John A. Katzenellenbogen*, Kendall W. Nettles, Hai-Bing Zhou*. ChemMedChem, 2012, 7 (6), 1094-1100. (IF: 2.835)6) Synthesis, biological evaluation and structure activity relationships of new estrogen receptor ligands based on a bridged oxabicyclic core embellished with arylsulfonamides. Manghong Zhu, Chen Zhang, Jerome C. Nwachukwu, Sathish Srinivasan, Valerie Cavett, Yangfan Zheng, Kathryn E. Carlson, Chune Dong, John A. Katzenellenbogen*, Kendall W. Nettles, Hai-Bing Zhou*. Org. Biomol. Chem., 2012, 10 (43), 8692-8700. (IF: 3.568)7) An Expedient Approach to Highly Enantioenriched Cyclic Nitrones Mediated by Robust and RecoverableC3-Symmetric Cinchonine-SquaramideCatalysts. Xin Han, Xiangfei Wu, Chang Min, Hai-Bing Zhou, Chune Dong*. RSC Advances 2012, 2 (19), 7501-7505. Highlighted by ChemInform, 2013, 44. (IF: 2.562)8) C3-Symmetric Cinchonine-Squaramideas New Highly Efficient, and Recyclable Organocatalyst for Enantioselective Michael Addition. Chang Min, Xin Han, Zongquan Liao, Xiangfei Wu, Hai-Bing Zhou, Chune Dong. Adv. Synth. Catal. 2011, 353 (14-15), 2715–2720. (IF: 6.048) Highlighted by ChemInform (2012, 43, 13).9) Metal-free Direct Amidation of Peptidyl Thiol Esters with α-Amino Esters. Hao Chen, Maomao He, Yaya Wang, Linhui Zhai, Yongbo Cui, Yangyan Li, Yan Li, Haibing Zhou*, Xuechuan Hong* and Zixin Deng. Green. Chem. 2011, 13, 2723-2726. (IF: 6.320)10) A Novel C3-Symmetric Prolinol-Squaramide Catalyst for the Asymmetric Reduction of Ketones by Borane. Xiang-Fei Wu, Chang Min, Hai-Bing Zhou, Chune Dong. Tetrahedron Asymmetry 2011, 22 (16-17), 1640–1643. (IF: 2.652)11) Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids from chiral imines of trifluoropyruvate, Qiao-Qiao Min, Chun-Yang He, Haibing Zhou and Xingang Zhang, Chem. Comm. 2010, 46, 8029-8031. (IF: 5.787)12) Imaging progesterone receptor in breast tumors: Synthesis and receptor binding affinity of fluoroalkyl-substituted analogs of Tanaproget. Hai-Bing Zhou, Jae Hak Lee, Christopher G. Mayne, Kathryn E. Carlson, John A. Katzenellenbogen, J. Med. Chem. 2010, 53 (8), 3349–3360. (IF: 5.207)13) Development of [F-18]Fluorine-Substituted Tanaproget as a Progesterone Receptor Imaging Agent for Positron Emission Tomography. Jae Hak Lee, Hai-bing Zhou, Carmen S. Dence, Kathryn E. Carlson, Michael J. Welch, John A. Katzenellenbogen, Bioconjugate Chem. 2010, 21 (6), 1096-1104. (IF: 5.002)14) Analogs of methyl-piperidinopyrazole (MPP): Antiestrogens selective activity.with estrogen receptor Hai-Bing Zhou, Kathryn E. Carlson, Fabio Stossi, Benita S. Katzenellenbogen, John A. Katzenellenbogen. Bioorg. Med. Chem. Lett. 2009, 19 (1), 108-110. (IF: 2.650)15) Bromination from the Macroscopic Level to the Tracer Radiochemical Level: 76Br Radiolabeling of Aromatic Compounds via Electrophilic Substitution. Dong Zhou, Haibing Zhou, Carl C. Jenks, Jason S. Lewis, John A. Katzenellenbogen, and Michael J. Welch. Bioconjugate Chem. 2009, 20 (4) 808-816. (IF: 4.350)16) Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-γ ligands: potential positron emission tomography imaging agents. Byung Chul Lee, Carmen S. Dence, Haibing Zhou, Ephraim E. Parent, Michael J. Welch, John A. Katzenellenbogen. Nucl. Med. Biol. 2009, 36 (2) 147-153. (IF: 2.456)17) NFkB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. K. W. Nettles, J. B. Bruning, G. Gil, J. Nowak, S. K. Sharma, J. B. Hahm, K. Kulp, R. B. Hochberg, H. B. Zhou, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Y. Kim, A. Joachmiak, G. G. Greene, Nature Chemical Biology 2008, 4 (4), 241-247. (IF: 14.612)18) Elemental Isomerism: A Boron-Nitrogen Surrogate for a Carbon-Carbon Double Bond Increases the Chemical Diversity of Estrogen Receptor Ligands. Hai-Bing Zhou, Kendall W. Nettles, John B. Bruning, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Kathryn E. Carlson, Fabio Stossi, Benita S. Katzenellenbogen, Geoffrey L. Greene and John A. Katzenellenbogen, Chemistry & Biology 2007, 14 (6), 659-669. (IF: 5.718)19) Bicyclo[2.2.2]octanes: Close Structural Mimics of the Nuclear Receptor-binding Motif of Steroid Receptor Coactivators. Hai-Bing Zhou, Margaret L. Collins, Jillian R. Gunther, John S. Comninos and John A. Katzenellenbogen, Bioorg. Med. Chem. Lett. 2007, 17 (15), 4118-4122. (IF: 2.604)20) Structure-Guided Optimization of Estrogen Receptor Binding Affinity and Antagonist Potency of Pyrazolopyrimidines with Basic Side Chain. Hai-Bing Zhou, Shubin Sheng, Dennis R. Compton, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Kathryn E. Carlson, B. S. Katzenellenbogen, Kendall W. Nettles, Geoffrey L. Greene and John A. Katzenellenbogen, J. Med. Chem. 2007, 50 (2), 399-403. (IF: 4.895)21) Synthesis and Evaluation of Estrogen Receptor Ligands with Bridged Oxabicyclic Cores Containing a Diarylethylene Motif: Estrogen Antagonists of Unusual Structure. Hai-Bing Zhou, John S. Comninos, Fabio Stossi, Benita S. Katzenellenbogen, and John A. Katzenellenbogen, J. Med. Chem. 2005, 48 (23), 7261-7274. 2012年珞珈学者特聘教授2010年药明康德生命化学研究奖2009年教育部新世纪优秀人才