李晓杨

博士

副 教 授

硕士生导师

科  室：

药物合成研究室

办公电话：

电子邮箱：

lixiaoyang@ouc.edu.cn

联系地址：

山东省青岛市崂山区香港东路23号中国海洋大学浮山校区

研究方向：

1. 基于靶点的药物设计、合成及活性研究

2. 基于HDAC的抗AML药物的研发

3. 以HDAC抑制剂抗肿瘤机制为导向的多靶点小分子的研究

个人简介

2019年7月经中国海洋大学“青年英才工程”第二层次引进在威廉希尔工作，研究方向为基于靶标的合理药物设计、合成及活性研究，包括选择性HDAC抑制剂，基于HDAC抑制剂抗肿瘤机制的多靶点小分子。近五年来，在J Med Chem, Eur Med Chem, Bioorg Med  Chem, Adv Cancer Res.等杂志 发表SCI论文32篇，申请专利9项，6项已被授权。主持和参与多项国家和省部级基金项目。

教育背景

2011.09~2016.06

山东大学

药物化学

博士

2007.09~2011.06

山东大学

药学

学士

工作经历

2019.07 ~至今

中国海洋大学 威廉希尔

副教授

2016.08~2019.06

美国南卡罗来纳医科大学

博士后

学术兼职

Journal of Medicinal Chemistry  (IF:6.205) , European Journal of Medicinal Chemistry (IF: 5.573) ,Bioorganic Medicinal Chemistry  (IF:2.881)审稿人。

中国药学会会员

承担课程

药物化学（本科生课程）

高等药物化学（研究生课程）

研究进展

组蛋白去乙酰化酶（HDACs）的突变和异常表达会导致多种疾病的发生，尤其是肿瘤，这使HDACs成为了重要的抗肿瘤靶点，越来越多的组蛋白去乙酰化酶抑制剂（HDACIs）  被开发出来用于肿瘤的治疗。由于不同HDAC亚型在肿瘤的发生发展过程中起到不同的作用，与此同时，每一种HDAC都有自己正常的生理学功能。所以选择性抑制剂被认为具有更好的特异性及较小的毒副作用。本课题组的主要研究方向为结合临床上或研究中的已知HDACIs的优势药效团和HDACs酶活性中心结构特点，设计、合成了全新骨架的HDACIs，并对不同的锌离子螯合基团进行探索，在不断的改造和优化过程中得到高效、高选择性以及体内药代动力学性质良好的分子，并探索其在疾病治疗上的潜在应用价值。另外，本课题组的研究方向也包括对HDAC选择性抑制剂对酶的结合模式及抗肿瘤作用机制的研究。

急性髓性白血病（Acute  myeloid leukemia, AML）是成年人中最常见的一类白血病。在现行的药物治疗下，60岁以上的患者（占患者群体的65%以上）五年生存率仅为5-15%，因此，临床急需安全有效的治疗AML的药物。Class ⅠHDACs对白血病及淋巴瘤细胞的增殖、迁徙和转移具有重要的作用。文献已经报道HDAC抑制剂具有体内外抗AML的作用。目前，已上市和在研的Class Ⅰ选择性HDAC抑制剂绝大多数均以异羟肟酸和邻苯二胺为螯合基团，普遍存在活性中等、药代动力学性质不理想等局限性。根据目前HDAC抑制剂的不足，本课题组结合目前临床上活性最好的HDAC抑制剂panobinostat的结构，改造其螯合基团异羟肟酸为酰肼，设计合成了一系列化合物。代表性化合物13a的酶活及对AML的细胞活性均在低纳摩尔级，并且在亚型选择性、药代动力学性质及安全性上较先导化合物均有明显提升。另外，13a结合HDAC1和HDAC3的变构位点，为变构抑制剂。抗白血病机制研究发现，13a的抗肿瘤活性具有FLT3和p53依赖性，在wt-p53 FLT3-ITD MV4-11细胞中，13a抑制FLT3通路，下调促凋亡蛋白c-Flip和XIAP，引发细胞凋亡；而在wt-FLT3或 p53-null 细胞中，13a则没有上述作用。

代表性成果

代表性论文

1.       Xiaoyang Li^#*, Yuqi Jiang^#, Yuri K. Peterson, Tongqiang  Xu, Richard A. Himes, Xin Luo, Guilin Yin, Elizabeth S. Inks, Nathan Dolloff,  Stephanie Halene, Sherine  S. L. Chan, and C. James Chou*.Design of  Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD  Dependency in Antileukemia Activity. J  Med Chem. 2020, 28; 63(10):5501-5525. 

2.       Xiaoyang Li*,  Richard A. Himes, Lyndsey C. Prosser, Charleston F. Christie, Emma Watt,  Sharon F. Edwards, Cameron Metcalf, Peter West, Karen Wilcox, Sherine S. L. Chan*, and C. James Chou*. Discovery of the  first Vitamin K analog as a potential treatment of pharmacoresistant  seizures. J Med Chem. 2020 63(11):5865-5878.

3.       Lihui Zhang^#, Xiaoyang Li^#,  Yiming Chen, Minghui Wan,  Qixiao Jiang, Li Zhang, C. James Chou, Weiguo Song and Lei Zhang*. Discovery of  N-(2-Aminophenyl)-4-(bis(2-chloroethyl)amino)  Benzamide as a Potent Histone Deacetylase Inhibitor. Front Pharmacol.2019; 10: 957.

4.       Xiaoyang Li, Yuri K. Peterson, Elizabeth S. Inks, Richard A. Himes,Jiaying Li,Yingjie Zhang, Xiujie  Kong, and C. James Chou*.Class I HDAC Inhibitors  Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells  Depending on Their p53 Status. J Med Chem. 2018; 61(6):2589-2603.

5.       Xiaoyang Li^#, Yingjie Zhang^#*, Yuqi Jiang, Jingde Wu, Elizabeth S. Inks, C. James Chou,  Shuai Gao, Jinning Hou, Qinge  Ding, Jingyao Li, Xue  Wang, Yongxue Huang, Wenfang  Xu. Selective HDAC inhibitors with potent  oral activity against leukemia and colorectal cancer: Design,  structure-activity relationship and anti-tumor activity study. Eur J Med Chem.2017; 134:185-206.

6.       Xiaoyang Li, Jinning  Hou, Xiaoguang Li, Yuqi Jiang, Xueliang Liu,  Weiwei Mu, YimingJin,  Yingjie Zhang*, Wenfang Xu*. Development of 3-Hydroxy cinnamamide-Based  HDAC Inhibitors with Potent in vitro  and in vivo Anti-tumor Activity. Eur J Med Chem. 2015; 7:628-637.

7.       Xiaoyang Li, Jingde Wu, Xiaoguang Li, Weiwei Mu, Xueliang Liu, YimingJin, Wenfang Xu, Yingjie Zhang*.  Development of N-hydroxy  benzamide derivatives with indole-containing cap group as histone  deacetylases inhibitors. Bioorg Med Chem.2015; 23(19):6258-6270.

8.       Xiaoyang Li, Elizabeth S. Inks, Xiaoguang Li,Jinning Hou,C. James Chou,Jian Zhang,Yuqi Jiang,Yingjie Zhang*, and  Wenfang Xu*. Discovery of the first N-hydroxycinnamamide -based  histone  deacetylase 1/3 dual inhibitors with potent oral antitumor  activity.J Med Chem. 2014; 57(8):3324-3334.

9.       Xiaoyang Li, Jian Zhang, YuanchaoXie, Yuqi Jiang, Zhang  Yingjie* and Wenfang  Xu*. Progress of HDAC inhibitor panobinostat in the treatment of cancer. Curr Drug Targets. 2014; 15(6):622-634.

10.  Xiaoyang Li and Wenfang Xu^*. HDAC1/3 dual  selective inhibitors-new potential therapeutic agent in the treatment of  cancer. Drug Discov Ther. 2014; 8(5):225-228.

11.  Jesse J. McClure, Xiaoyang Li, C. James Chou^*.  Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics. Adv Cancer Res.2018;  138: 183-211.

12.  Yuqi Jiang, Xiaoyang Li, Jinning Hou, Yongxue Huang,Xuejian Wang, Yuping Jia,Qingwei Wang,Wenfang Xu,Jian Zhang,Yingjie Zhang^*.Synthesis and biological characterization of  ubenimex-fluorouracil conjugates for anti-cancer therapy. Eur J Med Chem.2018; 143: 334-347.

13.  Xue  Wang,Xiaoyang Li, Jingyao Li, Jinning Hou, Ying  Qu, Chenggong Yu, Feng He, Wenfang Xu, Jingde Wu^*. Design, synthesis, and preliminary  bioactivity evaluation of N1 -hydroxyterephthalamide  derivatives with indole cap as novel histone deacetylase inhibitors. Chem Biol Drug  Des.2017;  89(1):38-46.

14.  Shuai  Gao, Xiaoyang Li, Jie Zang,Department of Medicinal Chemistry, School of  Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, ChinaWenfang Xu^*, Department  of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong  University, 44 West Culture Road, 250012 Ji'nan,  Shandong, ChinaYingjie  Zhang^*. Preclinical  and clinical studies of chidamide (CS055/HBI-8000),  an orally available subtype-selective HDAC inhibitor for cancer therapy. Anticancer Agents  Me.2017; 17: 802-812.

15.  Yuqi Jiang, Xiaoyang Li, Jinning Hou,Yongxue  Huang,Yuping  Jia,Mingming  Zou,Jian  Zhang,Xuejian  Wang,Wenfang  Xu^*,Yingjie  Zhang^*. Discovery of BC-01, a novel mutual prodrug  (hybrid drug) of ubenimex and fluorouracil as anticancer agent. Eur J Med Chem.2016; 121:649-57.

16.  Jingyao Li, Xiaoyang Li, Xue Wang, Jinning Hou, Jie Zang, Shuai Gao, Wenfang Xu^*,Yingjie Zhang^*.  PXD101 analogs with L-phenylglycine-containing branched cap as histone  deacetylase inhibitors. Chem Biol Drug Des.2016; 88(4):574-584.

17.  Yuqi  Jiang, Xiaoyang Li, Xue Wang, Zhonglan Wang, Jian  Zhang, Jingde Wu, Wenfang  Xu^*. Design, synthesis, and biological characterization of  tamibarotene analogs as anticancer agents. Chem Biol Drug  Des.2016; 88(4):542-555.

18.  Jian  Zhang, Xiaoyang Li, Yuqi  Jiang, Jinhong Feng, Xiaoguang Li, Yingjie Zhang  and Wenfang Xu^*. Design, synthesis and  preliminary evaluation of α-sulfonyl γ-(glycinyl-amino)  proline peptidomimetics as matrix metalloproteinase inhibitors. Bioorg Med Chem. 2014; 22(11):3055-3064.

19.  Xuewu  Liang, Jie Zang, Xiaoyang Li, Shuai Tang, Min Huang, MeiyuGeng, C. James Chou, Chunpu Li,  Yichun Cao, Wenfang Xu,  Hong Liu,*, and Yingjie Zhang*. Discovery of Novel  Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the  Treatment of Hematological Malignancies. J.  Med. Chem. 2019, 62, 3898−3923.

20.  Yuqi Jiang, Xiaogang Li, Xiaoyang Li, Jinning  Hou, Yongzheng  Ding, Jian  Zhang, Wenfang  Xu, Yingjie  Zhang^*. Discovery of Multi-target Anticancer  Agents Based on HDAC Inhibitor MS-275 and 5-FU. Med Chem.2016; 12(1):30-6.

21.  Yuqi  Jiang, Jinning Hou, Xiaoyang Li, Yongxue Huang,Xuejian Wang,Jingde Wu,Jian Zhang,Wenfang Xu,Yingjie Zhang^*.  Discovery of a novel chimeric ubenimex–gemcitabine with potent oral antitumor  activity. Bioorg Med Chem. 2016; 24(22):5787-5795.

22.  Yuqi Jiang, Jinning Hou, Xiaoyang Li, Wenfang Xu* and Yingjie Zhang*. Design, Synthesis and  Biological Evaluation of Novel Tamibarotene Derivative as Multitarget  Anticancer Agent. Letters in Drug Design & Discovery,2016, 13, 729-733.

23.  Feng  He, Yingying Ran, Xiaoyang Li, Defeng  Wang, Qiuqiong Zhang, JiahuiLv, Chenggong Yu, Ying Qu, Xiangna  Zhang, Ana Xu, Chao Wei, C. James Chou, Jingde Wu,  Design, synthesis and biological evaluation of dual-function inhibitors targeting  NMDAR and HDAC for Alzheimer’s disease. Bioorganic Chemistry, 2020, 103,104109.

24.  Ana  Xu, Feng He, Xiangna Zhang, Xiaoyang Li, Yingying Ran, Chao Wei, C. James Chou,Rui Zhang, Jingde Wu.  Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment  of Alzheimer’s  disease: Design, synthesis, and biological evaluation. Bioorganic Chemistry, 2020, 98, 103721

25.  Jie Zang, Xuewu Liang, Yongxue Huang, Yuping Jia, Xiaoyang Li, Wenfang Xu, C. James Chou, and Yingjie Zhang*. Discovery  of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer  Epigenetics and Angiogenesis Simultaneously. J Med Chem. 2018; 61(12):5304-5322.

26.  Daniel  J Herr, MauhamadBaarine,  Sverre E Aune, Xiaoyang Li, Lauren E. Ball, John J. Lemasters, Craig C. Beeson, James C. Chou, Donald R. Menick^*, HDAC1 localizes to  the mitochondria of cardiac myocytes and contributes to early cardiac  reperfusion injury. J  Mol Cell Cardiol. 2018; 114: 309-319.

27.  Jinning Hou,  Kang Jin, Jin Li, Yuqi Jiang, Xiaoyang Li, Xuejian Wang, Yongxue Huang,  Yingjie Zhang, Wenfang Xu^*. LJNK, an  indoline-2,3-dione-based aminopeptidase N inhibitor with promising antitumor  potency. Anticancer Drugs. 2016;27(6):496-507.

28.  Jia Jia, Eun Je Jeon, Mei Li, Dylan  J. Richards, Soojin Lee, Youngmee  Jung, Ryan W. Barrs, Robert Coyle, Xiaoyang Li, James C. Chou, Michael J. Yost, Sharon  Gerecht, Seung-Woo Cho, Ying Mei, Evolutionarily conserved sequence motif  analysis guides development of chemically defined hydrogels for therapeutic  vascularization. SCIENCE ADVANCES, 2020; 6 :  eaaz5894

29.  Shuai  Gao, Jie Zang, Qianwen Gao,  Xuewu Liang, Qinge Ding, Xiaoyang Li, Wenfang  Xu, C. James Chou, YingjieZhang^*.  Design, synthesis and anti-tumor activity study of novel histone deacetylase  inhibitors containing isatin-based caps and  o-phenylenediamine-based zinc binding groups. Bioorg Med Chem. 2017; 25(12): 2981-2994.

30.  Qin-ge Ding, Jie Zang, Shuai Gao, Qianwen Gao, Wenwen Duan, Xiaoyang Li, Wenfang  Xu, Yingjie Zhang. Nitric oxide donor hybrid compounds as promising  anticancer agents. Drug DiscovTher.  2017; 10(6): 276-284.

31.  Wenwen  Duan, Jin Li, Elizabeth S Inks, C James Chou, Yuping Jia, Xiaojing Chu, Xiaoyang Li, Wenfang Xu^*, Yingjie Zhang^*.  Design, synthesis, and antitumor evaluation of novel histone deacetylase  inhibitors equipped with a phenylsulfonylfuroxan  module as a nitric oxide donor. 2015;  J Med Chem. 58 (10): 4325-4338.

出版著作

专利

1.        徐文方, 李晓杨, 张颖杰.一种含有吲哚的肉桂酰胺类组蛋白去乙酰化酶抑制剂及其制备方法和应用. 2015.04.22, 中国,  CN103467359B.

2.        张颖杰，李晓杨，徐文方. 含有色氨酸基本骨架的邻苯二胺类选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用. 2018.10.30, 中国，CN105669520B.

3.        Donald R. Menick;  Chung-Jen James Chou; Daniel Herr; Xiaoyang Li;  HDAC INHIBITORS AND USES THEREOF, 2020-7-7, 美国, US 10,703,737 B2.

4.        张颖杰，徐文方，江余祺，李晓杨，侯金宁，丁永正. 多靶点型他米巴罗汀衍生物及其制备方法和应用. 2015.12.03, 中国，CN105175285A

5.        吴敬德, 王雪，曲颖，江余祺，李晓杨. 一种以 Raf/MEK/ERK 和PI3K/Akt为靶点的双通道抑制剂. 2016.08.10, 中国，CN103948587B.

6.        Wenfang Xu, Yuqi Jiang, Yingjie Zhang, Mingming  Zou, Jinning Hou, Jin Li,  Xuejian Wang, Xiaoyang Li. Multi-targeted Ubenimex Prodrug Derivative And Preparation Method And Use Thereof. JP:2017.12.27  US:2018.01.09 EP:2018.09.26, US9861703B2, JP6254264B2, EP 2947070B2,  WO2014194848A1. 美国，日本，欧洲.

7.    徐文方; 张剑; 江余祺; 徐晓铂; 李晓杨; 谭乐巧; 黄永学; 王学健;  MULTIFUNCTIONAL IMMUNITY TARGETED-MICROMOLECULE ANTI-CANCER MEDICINE  BESTAZOMIB (BESTAZOMIB) AND PREPARATION METHOD AND APPLICATION THEREOF,  2019-8-5, WIPO, PCT/CN2019/099305.

项目课题

1.     中国海洋大学“青年英才工程”第二层次科研基金，2019-2022，在研，主持

2.     山东省自然科学基金（ZR2020QH343），2021-2024，在研，主持

3.     山东省重大科技创新工程课题（2020CXGC010503）, 在研，子课题负责人

4.     国家自然科学基金面上项目（81973232），2020-2023，在研，参与

5.     山东省重大科技创新工程课题（2018SDKJ0403-1）, 在研，参与