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科研PI

云彩红 教授

1. 个人简介:

云彩红,教授,教育部“新世纪优秀人才支持计划”入选者,现任生物化学与生物物理学系副主任、主持生物物理学科工作。截至2020年12月已发表责任作者研究论文31篇(含共同,其中回国以来26篇),总被引用次数3300余次:包括Nature 1篇、Cell 1篇、CancerCell 1篇、SciTransl Med 2篇、Nat Commu 1篇、AngewChemInt Ed Engl 1篇、PNAS 1篇、Gene Dev 1篇、Oncogene 1篇和J Med Chem 5篇。既往工作偏重于结构药理学研究和三维结构辅助的合理药物设计,与国内外药物化学专家共同完成备选新药研发十余项;近期工作逐步偏重于应用冷冻电子显微镜技术和X-射线晶体学技术对重要生物大分子体系进行结构与功能关系研究。

云彩红教授在人表皮生长因子受体(EGFR)和肺癌相关EGFR突变领域做了多年工作:研究了一系列EGFR突变致癌的分子机理(Cancer Cell, 2007,封面故事)以及EGFR活性调控的分子机制(Cell, 2016);首次阐明了EGFR第一代耐药性突变T790M导致耐药的分子机理、提出克服T790M耐药的新药研发的三大策略(PNAS, 2008);并作为主要贡献者两次参与完成抗EGFR耐药性突变的里程碑式候选新药研发,包括全球第一个选择性抑制第一代EGFR耐药性突变XXX/T790M的化合物WZ4002(“第三代药”,见Nature, 2009)和全球第一个选择性抑制EGFR第二代耐药性突变L858R/T790M/C797S(该突变对WZ4002、CO-1686和AZD9291等“第三代药”耐药)的化合物EAI045(“第四代药”,见Nature, 2016),在这一系列研究工作中,发展了一套基于结构药理学研究的精准药物设计技术。最近云彩红教授主持了对RNA质量控制相关的NrdE2/Mtr4蛋白复合体(GenesDev, 2019)、植物碳糖基转移酶TcCGT1(AngewChemInt Ed Engl, 2019)和DNA损伤修复相关的HPF1/PARP1蛋白复合体(NatCommu, 2020)的结构与功能关系研究。


2. 研究方向与领域:

(1)结构生物学:实验测定重要生物大分子及其复合物的精确三维结构,阐明它们发挥功能和自我调控的结构基础与分子机制

(2)结构药理学:利用结构生物学研究手段测定靶标和活性化合物的复合物结构,回答药物分子对靶标具备亲和力和选择性的结构基础,阐明靶标突变导致耐药的分子机制

(3)药物分子的精准定向设计:在结构药理学研究的指导下进行原始创新性药物从头设计和精准定向改构


3. 实验室成员:(附全家福一张)

教工:

梁令,讲师

孔璐璐,主管技师

赵鹏,博士后研究助理

吴亚闯,博士后研究助理

学生:

何杏,张月明,张群,赵超然,陈丹丹,高浩萌


4. 主要代表作:

(1)Sun FH(#), Zhao P(#), Zhang N, Kong LL, Wong CCL and Yun CH(*), HPF1 remodels PARP1 active site for ADP-ribosylation of histones on serine, Nat Commu, accepted

(2)Yan XE(#), Ayaz P(#), Zhu SJ(#), Zhao P(#), Liang L, Zhang CH, Wu YC, Li JL, Choi HG, Huang X, Shan Y(*), Shaw DE(*), Yun CH(*). Structural Basis of AZD9291 Selectivity for EGFR T790M. J Med Chem. 2020 Aug 13;63(15):8502-8511.

(3)Shen J(#), Zhang T(#), Zhu SJ(#), Sun M, Tong L, Lai M, Zhang R, Xu W, Wu R, Ding J, Yun CH(*), Xie H(*), Lu X(*), Ding K(*). Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S). J Med Chem. 2019 Aug 8; 62(15): 7302-7308.

(4)Yang J(#), Shibu MA(#), Kong L(#), Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH(*), Huang CY(*), Ding K(*), Lu X(*). Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors. J Med Chem. 2020 Mar 12;63(5):2114-2130.

(5)He JB(#), Zhao P(#), Hu ZM, Liu S, Kuang Y, Zhang M, Li B, Yun CH(*), Qiao X(*), Ye M(*). Molecular Characterization and Structural Basis of a Promiscuous C-Glycosyltransferase from Trolliuschinensis. AngewChemInt Ed Engl. 2019 Aug 12;58(33):11513-11520.

(6)Wang J(#), Chen J(#), Wu G(#), Zhang H(#), Chen S(#), Du X, Zhang L, Wang K, Fan J, Gao S, Wu X, Zhang S, Kuai B, Zhao P, Chi B, Wang L, Li G, Wong CCL, Zhou Y, Li J(*), Yun CH(*), Cheng H(*). NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction. Genes Dev. 2019 May 1;33(9-10):536-549.

(7)Song C(#), Liang L(#), Jin Y, Li Y, Liu Y, Guo L, Wu C, Yun CH(*), and Yin Y(*), RCC2 is a novel p53 target in suppressing metastasis, Oncogene, 2018 Jan 4;37(1):8-17.

(8)Chang Y(#), Lu X(#), Shibu MA(#), Dai YB(#), Luo J, Zhang Y, Li Y, Zhao P, Zhang Z, Xu Y, Tu ZC, Zhang Q, Yun CH(*), Huang CY(*), Ding K(*), Structure-Based Design of N-(3-((1H-pyrazolo[3, 4-b]pyridin-5-yl)ethynyl) Benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors, J Med Chem. 2017 Jul 13;60(13):5927-5932.

(9)Wang A(#), Li X(#), Wu H(#), Zou F(#), Yan XE(#), Chen C, Hu C, Yu K, Wang W, Zhao P, Wu J, Qi Z, Wang W, Wang B, Wang L, Ren T, Zhang S, Yun CH(*), Liu J(*), Liu Q(*). Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode. J Med Chem. 2017 Apr 13;60(7):2944-2962.

(10)Fan F(#), He Z(#), Kong LL(#), Chen Q(#), Yuan Q(#), Zhang S, Ye J, Liu H, Sun X, Geng J, Yuan L, Hong L, Xiao C, Zhang W, Sun X, Li Y, Wang P, Huang L, Wu X, Ji Z, Wu Q, Xia NS, Gray NS, Chen L, Yun CH(*), Deng X(*) and Zhou D(*), Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration, SciTransl Med, 2016 Aug 17;8(352):352ra108.

(11)Anastasi S(#), Zhu SJ(#), Ballarò C, Manca S, Lamberti D, Wang LJ, Alemà S, Yun CH(*), Segatto O(*). Lack of Evidence that CYTH2/ARNO Functions as a Direct Intracellular EGFR Activator. Cell. 2016 May 19;165(5):1031-4.

(12)Jia Y(#), Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, Palakurthi S, Jang J, Lelais G, DiDonato M, Bursulaya B, Michellys PY, Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Jänne PA, Eck MJ(*), Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, Nature. 2016 May 25;534(7605):129-32.

(13)Liu L(#), Chen JY(#), Yang B, Wang FH, Wang YH(*), Yun CH(*),Active-State Structures of a Small Heat-Shock Protein Revealed a Molecular Switch for Chaperone Function, Structure, 2015 Nov 3;23(11):2066-75.

(14)Yasuda H(#), Park E(#), Yun CH(#), Sng NJ, Lucena-Araujo AR, Yeo WL, Huberman MS, Cohen DW, Nakayama S, Ishioka K, Yamaguchi N, Hanna M, Oxnard GR, Lathan CS, Moran T, Sequist LV, Chaft JE, Riely GJ, Arcila ME, Soo RA, Meyerson M, Eck MJ(*),Kobayashi SS(*), Costa DB(*),Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer, SciTransl Med, 2013 Dec18;5(216):216ra177.

(15)Zhou W(#), Ercan D(#), Chen L(#), Yun CH(#), Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS(*), Jänne PA(*), Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature, 2009 Dec 24; 462(7276):1070-4.

(16)Yun CH(#), Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, and Eck MJ(*), The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, ProcNatlAcadSci USA, 2008Feb 12; 105(6):2070-5.

(17)Yun CH(#), Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, and Eck MJ(*), Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity, Cancer Cell, 2007 Mar; 11(3):217-27.


5. 联系方式:

云彩红

北京大学基础医学院生物化学与生物物理学系

Email:yunch@hsc.pku.edu.cn

电话:010-82805386