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2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S(Cys797 to Ser797)mutant

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Chinese Chemical Letters 2020年第5期31卷 1281-1287页

作者： Xianglong Hu Qiuju Xun Tao Zhang Su-Jie Zhu Qian Li linjiang tong Mengzhen Lai Tao Huang Cai-Hong Yun Hua Xie Ke Ding Xiaoyun Lu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE) School of PharmacyJinan UniversityGuangzhou 510632China Division of Antitumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Institute for Translational Medicine College of MedicineQingdao UniversityQingdao 266021China Department of Biochemistry and Biophysics Institute of Systems BiomedicineSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

Extensive structure-activity relationships(SARs)study of JND3229 was conducted to yield a series of new reve rsible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797 S *** of the most potent compound 6 i potently suppressed EGFRL858 R/T790 M/C797 S kinase with an IC50 value of 3.1 nmol/L,and inhibited the proliferation of BaF3 cells harboring EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S mutants with IC50 values of 290 nmol/L and 316 nmol/L,***,6 i dose-dependently induced suppression of the phosphorylation of EGFRL858 R/T790 M/C797 S and EGFR19 D/T790 M/C797 S in BaF3 *** 6 i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer(NSCLC)patients.

关键词： EGFRC797S mutant SARs 2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidine Clinical resistance Fourth-generation inhibitors

A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

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Cancer Communications 2024年第3期44卷 438-442页

作者： Yingqiang Liu linjiang tong Mengge Zhang Qi Zhang Qiupei Liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie Division of Antitumor Pharmacology&State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China University of Chinese Academy of Sciences BeijingP.R.China Department of Chemical and Environmental Engineering University of Nottingham Ningbo ChinaNingboZhejiangP.R.China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP.R.China Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandongP.R.China Small-Molecule Drug Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune *** in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug *** emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

关键词： alterations KRAS sarcoma

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4748-4764页

作者： Yingqiang Liu Zhengsheng Zhan Zhuang Kang Mengyuan Li Yongcong Lv Shenglan Li linjiang tong Fang Feng Yan Li Mengge Zhang Yaping Xue Yi Chen Tao Zhang Peiran Song Yi Su Yanyan Shen Yiming Sun Xinying Yang Yi Chen Shanyan Yao Hanyu Yang Caixia Wang Meiyu Geng Wenbin Li Wenhu Duan Hua Xie Jian Ding Division of Antitumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Medicinal Chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Neuro-oncology Cancer CenterBeijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Shanghai Runshi Pharmaceutical Technology Co. Ltd.Shanghai 201218China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan 528400China University of Chinese Academy of Sciences Beijing 100049China Hangzhou Institute for Advanced Study University of Chinese Academy of SciencesHangzhou 310024China

Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly *** studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM ***,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against ***1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in ***1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive ***,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM ***,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 *** a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I *** data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).

关键词： Small molecule inhibitor Glioblastoma VEGFR CSF1R Angiogenesis Macrophage Tumor microenvironment Immune-checkpoint inhibitor

Branched-chain amino acid transaminase 1 confers EGFRTKI resistance through epigenetic glycolytic activation

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Signal Transduction and Targeted Therapy 2024年第9期9卷 4103-4119页

作者： Tao Zhang Zilu Pan Jing Gao Qingqing Wu Gang Bai Yan Li linjiang tong Fang Feng Mengzhen Lai Yingqiang Liu Peiran Song Yi Ning Haotian Tang Wen Luo Yi Chen Yan Fang Hui Zhang Qiupei Liu Yudi Zhang Hua Wang Zhiwei Chen Yi Chen Meiyu Geng Hongbin Ji Guilong Zhao Hu Zhou Jian Ding Hua Xie Division of Antitumor Pharmacology&Analytical Research Center for Organic and Biological Molecules&State Key Laboratory of Drug Research&Small-Molecule Drug Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina University of Chinese Academy of Sciences BeijingChina Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanChina School of Pharmaceutical Sciences Southern Medical UniversityGuangzhouChina Shanghai Lung Cancer Center Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Chemical and Environmental Engineering University of NottinghamNingboChina School of Life Science and Technology ShanghaiTech UniversityShanghaiChina State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghaiChina

Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application(NDA)submission in *** substantial progress,acquired resistance to EGFR-TKIs remains a significant challenge,impeding the long-term effectiveness of therapeutic *** this study,we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models,and found a notable upregulation of branched-chain amino acid transaminase 1(BCAT1)expression in both osimertinib-and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC *** depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR ***,upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid(BCAA)metabolism and promoted alpha ketoglutarate(α-KG)-dependent demethylation of lysine 27 on histone H3(H3K27)and subsequent transcriptional derepression of glycolysis-related genes,thereby enhancing glycolysis and promoting tumor ***,we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 *** summary,our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC,thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

关键词： metabolism impaired resistance

新颖3,4-二氢-苯并[b]氧杂棘-5(2H)-酮类化合物的合成以及蛋白酪氨酸激酶抑制活性研究

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有机化学 2017年第6期37卷 1463-1472页

作者：侯桂革江成世刘红椿童林江彭霞季寅淳耿美玉肖伟龚景旭郭跃伟中国科学院上海药物研究所新药研究国家重点实验室上海201203 滨州医学院"方剂效应与临床评价"国家中医药管理局重点实验室烟台264003 济南大学生物科学与技术学院济南250022 江苏康源药业股份有限公司连云港222001

通过合成得到了一系列新颖的苯并[b]氧杂棘-5(2H)-酮类化合物单晶,结构经~1HNMR,^(13)CNMR和HREIMS确证,E-7-[(2,5-二羟基苯基)甲亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5(2H)-酮(8k)和E-7-[(2,3,4-三羟基苯基)亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5-(2H)-酮(8n)的结构经单晶X衍射方法进一步确证.系统测试了化合物对蛋白酪氨酸激酶(PTKs),如ErbB1,ErbB2,c-Met,ALK,FGFR1,RET和KDR等的抑制活性,结果表明含有邻苯二酚片段的化合物对蛋白酪氨酸激酶具有显著的抑制活性,其中E-7-[(3,4-二羟基苯基)甲亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5(2H)-酮(8i)对ErbB1和ErbB2的IC50分别为1.0和0.33μmol/L,8n对RET的IC_(50)为0.7μmol/L,7-[(3,4-二羟基苯基)甲基]氨基-2,3,4,5-四氢-苯并[b]氧杂棘-5-醇(10b)对ErbB2的IC_(50)为1.02μmol/L.

关键词： 3,4-二氢-苯并[b]氧杂棘-5(2H)-酮合成蛋白酪氨酸激酶抑制剂 ErbB1 ErbB2

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考虑预估驾驶行为的跟驰模型及其稳定性分析

重庆大学学报（自然科学版） 2016年第6期39卷 141-147页

作者：周桐郑林江刘卫宁重庆工程职业技术学院信息工程学院重庆402260 重庆大学计算机学院重庆400044

在OV模型的基础上,进一步考虑预估驾驶行为对车流的影响,提出一个新的跟驰模型以获得预估驾驶行为与交通拥堵的关系。通过对新模型进行稳定性分析得到了系统的临界稳定条件。数值仿真结果表明:新模型能够模拟诸如时停时走、系统临界相... 详细信息

在OV模型的基础上,进一步考虑预估驾驶行为对车流的影响,提出一个新的跟驰模型以获得预估驾驶行为与交通拥堵的关系。通过对新模型进行稳定性分析得到了系统的临界稳定条件。数值仿真结果表明:新模型能够模拟诸如时停时走、系统临界相变等实际交通现象,较OV模型更贴近于实际。同时,预估驾驶行为增强了交通流稳定性能,提高了车流陷入交通阻塞状态的阈值。最后以车速的平滑度和波动幅度最小为评价指标得到了新模型中预估参数的最优取值范围。

关键词：交通流交通拥堵跟驰模型预估驾驶行为

考虑多车稳态期望速度效应的拥堵控制跟驰模型

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重庆大学学报（自然科学版） 2018年第1期41卷 51-60页

作者：周桐郑林江刘卫宁唐毅周召敏重庆工程职业技术学院信息工程学院重庆402260 重庆大学计算机学院重庆400044

拥堵控制是智能交通系统的一个关键问题。基于Konishi等的研究成果,考虑多车稳态期望速度效应对车流运动特性的影响,提出一个新的拥堵控制跟驰模型。运用系统控制理论,得到系统保持稳定的判据。数值仿真结果表明:与前人研究成果相比,多... 详细信息

拥堵控制是智能交通系统的一个关键问题。基于Konishi等的研究成果,考虑多车稳态期望速度效应对车流运动特性的影响,提出一个新的拥堵控制跟驰模型。运用系统控制理论,得到系统保持稳定的判据。数值仿真结果表明:与前人研究成果相比,多车稳态期望速度效应对交通流具有更好的致稳作用,提高了车流陷入交通阻塞状态的阈值。因此,提出的模型较前人的成果能进一步缓解交通拥堵程度,使交通系统稳定性增强。

关键词：交通系统拥堵抑制跟驰模型多车稳态期望速度效应

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水面船舶运动姿态对声散射特性的影响

中国舰船研究 2023年第3期18卷 104-110,121页

作者：刘妍韩林江柴鹏程周富霖彭子龙江苏科技大学能源与动力学院江苏镇江212100 上海交通大学船舶海洋与建筑工程学院上海200240

[目的]为了进一步提高鱼雷通过声自导识别复杂水面目标的精度,对随机起伏海面及水面船舶运动姿态下的声散射特性进行模拟研究。[方法]基于Kirchhoff近似和六自由度运动分解合成的方法,建立水面船舶目标多路径声散射简化预报模型。在该... 详细信息

[目的]为了进一步提高鱼雷通过声自导识别复杂水面目标的精度,对随机起伏海面及水面船舶运动姿态下的声散射特性进行模拟研究。[方法]基于Kirchhoff近似和六自由度运动分解合成的方法,建立水面船舶目标多路径声散射简化预报模型。在该模型中,海面波浪对船舶六自由度运动幅度和周期的影响由经验统计值描述,通过旋转矩阵和平移矩阵,实现目标各顶点在连续运动状态下的坐标变换。基于此,利用所建预报模型,分析不同水平探测角下船舶六自由度运动分别对声散射特性的贡献度和影响。[结果]研究表明:横摇和艏摇对正横探测方位角的声散射影响较大,纵摇对艏、艉向声散射影响较大。此外,建立了船舶运动姿态与目标声散射回波特性的关系。[结论]研究结果可为声呐设备对水面目标主动声探测提供技术支撑。

关键词：水面船舶声散射特性运动姿态简化预报模型 Kirchhoff近似

基于视觉深度学习算法的变电站智能巡检应用研究

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吉林电力 2022年第4期50卷 1-4页

作者：赵振喜王朔刘春生郭玉福王朝辉武桐范恩洪侯林江国网吉林省电力有限公司长春130028 国网吉林省电力有限公司建设分公司长春130021 炜呈智能电力科技(杭州)有限公司杭州310000

针对变电站智能巡检,在变电站传统辅助系统及前期布设或配备的视频监控装置、机器人巡检、单兵作业装备等设备接入层基础上,通过边缘物联代理,以及人工智能(artificial intelligence, AI)分析服务器内置集成AI视觉分析算法和模型,构建... 详细信息

针对变电站智能巡检,在变电站传统辅助系统及前期布设或配备的视频监控装置、机器人巡检、单兵作业装备等设备接入层基础上,通过边缘物联代理,以及人工智能(artificial intelligence, AI)分析服务器内置集成AI视觉分析算法和模型,构建分析服务层,以实现变电站智能巡检设备状态实时监测、站端表计智能识别、环境智能实时监测、人员安全智能评估、安全作业监控、电子虚拟围栏等业务场景;同时,介绍了卷积神经网络主要技术路线,着重介绍了以站内烟火作为实例对视觉学习算法构建成熟实用的视觉学习模型,验证了其技术先进性、可行性,减少了变电站巡检人员工作量,提高了站内事故隐患分析和处理效率,从而较大地提高了变电站安全管理水平。

关键词：边缘物联代理卷积神经网络深度学习人工智能智能巡检图像标注