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Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

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药学学报:英文版 2023年第6期13卷 2715-2735页

作者： Pengyun Li Changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu shiyang sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li National Engineering Research Center for Strategic Drugs Beijing Institute of Pharmacology and Toxicology InstitutionBeijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China National Center for Protein Sciences(Beijing) Beijing Institute of LifeomicsState Key Laboratory of ProteomicsBeijing Proteome Research CenterBeijing 102206China Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation MedicineBeijing 100850China

Various c-mesenchymal-to-epithelial transition(c-MET) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras(PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC_(50) values and achieved picomolar DC_(50) values and>99% of maximum degradation(D_(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion.Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^(Y1230H) and c-MET^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

关键词： Cancer therapy Drug design c-MET Proteolysis targeting chimeras(PROTACs) Drug resistance

纳米二氧化硅强化聚合物凝胶对高温地层水的控制能力

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辽宁化工 2024年第4期53卷 510-513页

作者：周开浪王爱民卢伟孙诗洋王正福中海石油(中国)有限公司湛江分公司广东湛江524057

聚合物凝胶堵水是适用于非均质油藏堵水的常用方法。在恶劣的储层条件下聚合物凝胶系统的凝胶网络结构和交联时间容易受到影响。向其中添加纳米二氧化硅是一种有效的强化措施。介绍了纳米二氧化硅增强聚合物凝胶的黏度、胶凝时间、胶凝... 详细信息

聚合物凝胶堵水是适用于非均质油藏堵水的常用方法。在恶劣的储层条件下聚合物凝胶系统的凝胶网络结构和交联时间容易受到影响。向其中添加纳米二氧化硅是一种有效的强化措施。介绍了纳米二氧化硅增强聚合物凝胶的黏度、胶凝时间、胶凝强度以及在岩心中的堵水性能。结果显示,添加0.5%的纳米二氧化硅能够帮助凝胶弥补因高温和高矿化度而导致黏度损失,有效延长了聚合物凝胶的胶凝时间,提高了凝胶网络结构的热稳定性。在高温条件下,相比于单一聚合物凝胶的堵水性能,复合聚合物凝胶拥有更高的承压能力。

关键词：聚合物凝胶纳米二氧化硅堵水热稳定性

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油田老化油处理工艺研究及应用

化工管理 2024年第9期 153-158页

作者：周开浪凌宇谢进宜王爱民卢伟孙诗祥中海石油(中国)有限公司湛江分公司广东湛江524057

随着海上油田群滚动开发,南海西部某陆岸终端老化油逐步增多,老化油不仅占据大量罐容,还影响外输销售原油产品质量。针对老化油含水率高、乳化程度高和机械杂质含量高特点,因地制宜通过新增一套蝶式离心机并利用现有设备设施进行工艺流... 详细信息

随着海上油田群滚动开发,南海西部某陆岸终端老化油逐步增多,老化油不仅占据大量罐容,还影响外输销售原油产品质量。针对老化油含水率高、乳化程度高和机械杂质含量高特点,因地制宜通过新增一套蝶式离心机并利用现有设备设施进行工艺流程适应性改造,采取离心机离心分离预脱水、事故罐热化学沉降再脱水和原油稳定塔高温蒸馏精脱水三段处理工艺进行处理。通过该处理工艺,已累计处理老化油3万m3,处理后原油含水率≤0.5%,满足原油外输销售标准,应用效果良好。

关键词：老化油原油脱水含水率

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单点提油海管内检测适应性改造及应用

化工管理 2024年第13期 136-140页

作者：周开浪凌宇谢进宜丁勇超孙诗洋卢伟中海石油(中国)有限公司湛江分公司广东湛江524057

南海西部某陆岸终端单点提油海管由于未设计收发球筒装置,无法进行通球内检测,导致不能及时发现海管存在的各种缺陷,存在重大安全环保隐患。针对单点系泊系统特殊结构,通过自主改造设计安装简易立式双向收发二合一球筒并新增供排水通球... 详细信息

南海西部某陆岸终端单点提油海管由于未设计收发球筒装置,无法进行通球内检测,导致不能及时发现海管存在的各种缺陷,存在重大安全环保隐患。针对单点系泊系统特殊结构,通过自主改造设计安装简易立式双向收发二合一球筒并新增供排水通球流程,实现了海管正反向循环通球内检测功能。通过该适应性改造,完成了海管首次内检测,发现海管主要缺陷为陆岸管段外腐蚀并进行了加固修复,保障了海管安全环保可靠运行,同时创造经济效益1100万元,对类似海管内检测适应性改造具有一定的借鉴意义。

关键词：海管收发球筒内检测缺陷

某油气终端处理厂水资源消耗分析及节水减排措施

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化工管理 2024年第3期 56-60页

作者：周开浪凌宇丁勇超米占虎谢进宜孙诗洋中海石油(中国)有限公司湛江分公司广东湛江524057

随着海上油田群滚动开发以及当地政府关于加强水资源开发利用和保护方案的实施,南海西部某油气终端处理厂生产过程中水资源供需矛盾日趋凸显。通过对终端水系统基本情况、用水结构以及存在的问题进行分析,从工艺优化、设备更新换型、输... 详细信息

随着海上油田群滚动开发以及当地政府关于加强水资源开发利用和保护方案的实施,南海西部某油气终端处理厂生产过程中水资源供需矛盾日趋凸显。通过对终端水系统基本情况、用水结构以及存在的问题进行分析,从工艺优化、设备更新换型、输水管道检测、非常规水资源利用以及加强综合管理五个方面出发,提出并针对实施相应节水减排措施,实现了生产用水自给自足,保障了正常稳定清洁生产,并为相关企业节水减排提供了借鉴和依据。

关键词：水资源用水结构节水减排清洁生产

Digging out molecular markers associated with low salinity tolerance of Nannochloropsis oceanica through bulked mutant analysis

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Journal of Oceanology and Limnology 2020年第6期38卷 1867-1879页

作者： LIANG Sijie ZHANG Zhongyi LIU Hang GUO Li sun shiyang YANG Guanpin College of Marine Life Sciences Ocean University of China(OUC)Qingdao 266003China Key Laboratory of Marine Genetics and Breeding of Ministry of Education OUCQingdao 266003China College of Fisheries OUCQingdao 266003China Institute of Evolution and Marine Biodiversity OUCQingdao 266003China

Nannochloropsis oceanica is a marine microalgal species with both economic value and biological importance.It grows fast,contains rich oils,reproduces asexually,holds a small and haploidy genome,and is easy to be modified genetically.However,the genetic study of N.oceanica is scarce.Very less genetic bases of its traits have been deciphered,and no gene has been isolated from it with the function verified simultaneously via either genetic or reverse genetic approaches or both(de novo cloned).Changing medium salinity may aid to control harmful organisms met during large scale cultivation.As a stress,it may also facilitate the accumulation of desirable chemicals including fatty acids.In order to decipher the genetic basis of the low salinity tolerance of N.oceanica,we mutated N.oceanica with Zeocin.In total,five mutant bulks were constructed at equal number of cells,100 mutants each,which were tolerant to a discontinuous serial of salinities from that of 100%of f/2 to that of a mixture of 4%of f/2 and 94%of BG11.The bulks were genotyped through whole genome re-sequencing and analyzed with bulked mutant analysis(BMA)newly modified from bulked segregant analysis(BSA).In total,47 SNPs and 112 InDels were found to associate with the low salinity tolerance,and around them a set of low salinity tolerance associating genes were identified.A set of annotatable genes commonly found between control and different salinities indicated that the genes functioning in gene expression,energy metabolism and cellular structure may be involved in the low salinity tolerance.These associating molecular markers and genes around them were not enough for outlining the physiological mechanism underlining the tolerance;however they should aid to improve N.oceanica genetically.

关键词： Nannochloropsis oceanica bulked mutant analysis(BMA) low salinity tolerance

Transcriptome Responses of Hygromycin B Resistance Gene-Transformed, Hygromycin B-Adaptive and Wild Nannochloropsis oceanica Strains to Hygromycin B

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Journal of Ocean University of China 2020年第2期19卷 453-458页

作者： LIU Hang ZHANG Zhongyi LIANG Sijie GUO Li sun shiyang PAN Kehou YANG Guanpin College of Marine Life Sciences Ocean University of ChinaQingdao 266003China Laboratory of Applied Microalgae College of FisheriesOcean University of ChinaQingdao 266003China Institutes of Evolution and Marine Biodiversity Ocean University of ChinaQingdao 266003China Key Laboratory of Marine Genetics and Breeding of Ministry of Education Ocean University of ChinaQingdao 266003China

In order to decipher the hygromycin B tolerance and resistance mechanisms of Nannochloropsis oceanica,the transcriptome profiles of a transgenic strain carrying a randomly integrated hygromycin B resistant gene,a hygromycin B-adaptive strain and a wild type strain of N.oceanica were compared by transcriptome sequencing(RNA-seq)without referring to a high quality genome sequence.The results showed that the adaptive strain adapts to the hygromycin B existing environments mainly by intensifying the expressions of the efflux pump ABC and MFS superfamily transporter genes,thus reducing the intracellular concentration of hygromycin B.The transgenic strain obtains the hygromycin B resistance ability solely by expressing exogenous resistance gene.Accordingly,the screening and maintenance of N.oceanica transformants should be carried out at an antibiotics concentration higher than the adaptive threshold.Our findings can help the genetic modification of N.oceanica with the application of hygromycin B.

关键词： Nannochloropsis oceanica hygromycin B tolerance resistance transcriptome

Identification of Cinobufagin and Resibufogenin as Inhibitors of Enterovirus 71 Infection

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Chemical Research in Chinese Universities 2014年第6期30卷 953-958页

作者： CHEN Jiawen XU Lin sun shiyang ZHANG Huafei MA Tonghui SU Weiheng JIANG Chunlai National Engineering Laboratory for AIDS Vaccine Key Laboratory for Molecular Enzymology & Engineering Ministry of Education School of Life Seiences Jilin University Changchun 130012 P. R. China" College of Basic Medical Sciences Dalian Medical University Dalian 116044 t~ R. China

In this paper, cinobufagin and resibufogenin were found to inhibit enterovirus 71（EV71） infection in vitro in cell viability and plaque reduction assays. The 50% inhibitory concentrations（lCs0） of einobufagin and resibufoge- nin were （10.94±2.36） and （218±31） nmol/L, respectively, the 50% cytotoxic concentrations（CCs0） of them were （1277±223） and （1385±254） nmol/L, respectively, and the anti-EV71 selectivity index（SI50） of cinobufagin was 116.7, which are promisingly developed into drug. Using a VP1 detection assay and a constructed reporter luciferase, we found that cinobufagin and resibufogenin disrupted the synthesis of EV71 protein. However, neither of them inhibited EV71 RNA replication. Our study suggests that cinobufagin and resibufogenin are the promising candidates that should he fllrther investigated for the treatment of EV71 caused disease.

关键词： Enterovirus 71 Coxsackievirus A16 Cinobufagin Resibufogenin Chansu

Making the Pilot Project of Standardization as an Opportunity to Develop Shenzhen Public Meteorological Service Innovatively

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China Standardization 2011年第5期56卷 42-45页

作者： sun shiyang Shenzhen Meteorological Service Center (Lightning Protection Center)

The rapid development of the social economy and the urgent needs of building a low-carbon,ecologic and livable city ask for a higher requirement for urban meteorological service,which requires higher,better and more specialized service.To Shenzhen,the year of 2011 is featured by “Universiade” and “Quality”.In this year,the first national meteorological service standardization pilot and demonstration unit is stationed in Shenzhen,which has more far-reaching significance,richer connotation and heavier responsibility.In the meanwhile,it brings a historic opportunity for the innovative development of public meteorological service in Shenzhen.We will change the traditional ideas,break through the existing mode,make reforms as a forerunner,and innovatively develop the public meteorological service in Shenzhen.

关键词：城市气象服务服务创新深圳市标准化试点项目宜居城市