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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

《医学前沿（英文）》 2023年 第17卷 第2期   页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor     ErbB receptors     HM781-36B     nasopharyngeal carcinoma     molecular targeted therapy     cisplatin    

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Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging

null

《医学前沿（英文）》 2017年 第11卷 第4期   页码 449-461 doi: 10.1007/s11684-017-0589-5

摘要：

In recent years, unexpected outbreaks of infectious diseases caused by emerging and re-emerging viruses have become more frequent, which is possibly due to environmental changes. These outbreaks result in the loss of life and economic hardship. Vaccines and therapeutics should be developed for the prevention and treatment of infectious diseases. In this review, we summarize and discuss the latest progress in the development of small-molecule viral inhibitors against highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, Ebola virus, and Zika virus. These viruses can interfere with the specific steps of viral life cycle by blocking the binding between virus and host cells, disrupting viral endocytosis, disturbing membrane fusion, and interrupting viral RNA replication and translation, thereby demonstrating potent therapeutic effect against various emerging and re-emerging viruses. We also discuss some general strategies for developing small-molecule viral inhibitors.

关键词： emerging and re-emerging viruses     small-molecule inhibitor     coronavirus     Ebola virus     Zika virus     life cycle    

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Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

《医学前沿（英文）》 doi: 10.1007/s11684-023-1037-3

摘要： The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir–ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir–ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir–ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China’s homegrown anti-COVID-19 drugs.

关键词： COVID-19     antiviral drugs     mindeudesivir    

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Recent advances of small-molecule fluorescent probes for detecting biological hydrogen sulfide

《化学科学与工程前沿（英文）》 2022年 第16卷 第1期   页码 34-63 doi: 10.1007/s11705-021-2050-1

摘要： H2S is well-known as a colorless, acidic gas, with a notoriously rotten-egg smell. It was recently revealed that H2S is also an endogenous signaling molecule that has important biological functions, however, most of its physiology and pathology remains elusive. Therefore, the enthusiasm for H2S research remains. Fluorescence imaging technology is an important tool for H2S biology research. The development of fluorescence imaging technology has realized the study of H2S in subcellular organelles, facilitated by the development of fluorescent probes. The probes reviewed in this paper were categorized according to their chemical mechanism of sensing and were divided into three groups: H2S reducibility-based probes, H2S nucleophilicity-based probes, and metal sulfide precipitation-based probes. The structure of the probes, their sensing mechanism, and imaging results have been discussed in detail. Moreover, we also introduced some probes for hydrogen polysulfides.

关键词： hydrogen sulfide     fluorescent probe     reducibility     nucleophilicity     copper sulfide precipitate     hydrogen polysulfides    

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Genetic biosensors for small-molecule products: Design and applications in high-throughput screening

Qingzhuo Wang,Shuang-Yan Tang,Sheng Yang

《化学科学与工程前沿（英文）》 2017年 第11卷 第1期   页码 15-26 doi: 10.1007/s11705-017-1629-z

摘要： Overproduction of small-molecule chemicals using engineered microbial cells has greatly reduced the production cost and promoted environmental protection. Notably, the rapid and sensitive evaluation of the concentrations of the desired products greatly facilitates the optimization process of cell factories. For this purpose, many genetic components have been adapted into biosensors of small molecules, which couple the intracellular concentrations of small molecules to easily detectable readouts such as fluorescence, absorbance, and cell growth. Such biosensors allow a high-throughput screening of the small-molecule products, and can be roughly classified as protein-based and RNA-based biosensors. This review summarizes the recent developments in the design and applications of biosensors for small-molecule products.

关键词： biosensor     small molecule product     transcription factor     riboswitch     high-throughput screening    

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Bright future of polymerizing small-molecule acceptors in realizing high performance all-polymer solar

Qi Chen1 , Cen Zhang1 , Lingwei Xue1,2 , Zhi-Guo Zhang1

《化学科学与工程前沿（英文）》 2022年 第16卷 第10期   页码 1526-1529 doi: 10.1007/s11705-022-2161-3

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Discovery of small molecule degraders for modulating cell cycle

《医学前沿（英文）》   页码 823-854 doi: 10.1007/s11684-023-1027-5

摘要： The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

关键词： PROTAC     molecular glue     degrader     cell cycle     CDK     cyclin    

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Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

《医学前沿（英文）》 2020年 第14卷 第1期   页码 60-67 doi: 10.1007/s11684-019-0694-8

摘要： Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

关键词： BPTF     small molecule     epigenetics     non-small-cell lung cancer    

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Near-infrared benzodiazoles as small molecule environmentally-sensitive fluorophores

《化学科学与工程前沿（英文）》 2022年 第16卷 第1期   页码 128-135 doi: 10.1007/s11705-021-2080-8

摘要： The development of fluorophores emitting in the near-infrared spectral window has gained increased attention given their suitable features for biological imaging. In this work, we have optimised a general and straightforward synthetic approach to prepare a small library of near-infrared-emitting C-bridged nitrobenzodiazoles using commercial precursors. C-bridged benzodiazoles have low molecular weight and neutral character as important features that are not common in most near-infrared dyes. We have investigated their fluorescence response in the presence of a wide array of 60 different biomolecules and identified compound 3i as a potential chemosensor to discriminate between Fe2+ and Fe3+ ions in aqueous media.

关键词： fluorescence     probes     iron     screening     library    

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基于整合临床和动物实验的小分子筛选平台揭示经典方剂茵陈蒿汤治疗黄疸证显效状态下的活性化合物及潜在作用靶点 Article

熊辉, 张爱华, 郭雅静, 周小航, 孙晖, 杨乐, 方衡, 闫广利, 王喜军

《工程（英文）》 2021年 第7卷 第9期   页码 1293-1305 doi: 10.1016/j.eng.2020.12.016

摘要：

中药方剂化学组成高度复杂，其药理作用具有多成分、多靶点的特点，使得阐明其生物活性化合物极具挑战性。茵陈蒿汤被广泛用于治疗黄疸相关疾病。尽管近年来茵陈蒿汤的药效及活性成分被不断证实，但仍然缺乏对其效应成分、效应机制和功能靶点的深入系统分析，尤其是临床研究方面。本研究建立了一个整合临床和动物实验平台用于发现茵陈蒿汤的活性化合物和潜在靶点。首先采用基于超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-ToF-MS）技术的代谢组学方法结合中药血清药物化学方法揭示茵陈蒿汤的血清代谢谱和化学成分谱。此外，通过网络药理学和智能途径分析平台构建化合物-靶标-通路关联网络。最终发现茵陈蒿汤中8 个活性小分子与5 个核心靶点极度相关，并通过酶联免疫吸附测定实验进行生物学验证。结果表明茵陈蒿汤通过靶向胆固醇7α-羟化酶（CYP7A1）、多药耐药相关蛋白2（ABCC2）、多药耐药相关蛋白3（ABCC3）、尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）和法尼醇X受体（FXR）来调节包括初级胆汁酸生物合成、卟啉和叶绿素代谢以及胆汁分泌在内的代谢通路，从而发挥利胆退黄的作用。该整合策略可以成功地用于中药方剂活性小分子及其作用靶点的发现。

关键词： 有效性     活性化合物     小分子     靶点     中药     代谢组学    

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Design of nanocarriers for efficient cellular uptake and endosomal release of small molecule and nucleic

Vaibhav Mundra, Ram I. Mahato

《化学科学与工程前沿（英文）》 2014年 第8卷 第4期   页码 387-404 doi: 10.1007/s11705-014-1457-3

摘要： There are many challenges in developing efficient and target specific delivery systems of small molecule and nucleic acid drugs. Cell membrane presents one of the major barriers for the penetration of hydrophilic macromolecules across the plasma membrane. Nanocarriers have been designed to enhance their cellular uptake via endocytosis but following their cellular uptake, endosomal escape is the rate limiting step which restricts the value associated with the enhanced uptake by nanocarriers. Viruses are an excellent model for efficient cytosolic delivery by nanocarriers. Viruses exploit intracellular cues to release the genome to cytosol. In this review, we first discuss different endocytic uptake pathways and endosomal escape mechanisms. We then summarize the existing tools for studying the intracellular trafficking of nanocarriers. Finally, we highlight the important design elements of recent virus-based nanocarriers for efficient cellular uptake and endosomal escape.

关键词： nanocarrier     cellular uptake     endosomal release     nucleic acid drug    

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Recent advances in small molecule fluorescent probes for simultaneous imaging of two bioactive molecules

Yongqing Zhou, Xin Wang, Wei Zhang, Bo Tang, Ping Li

《化学科学与工程前沿（英文）》 2022年 第16卷 第1期   页码 4-33 doi: 10.1007/s11705-021-2041-2

摘要： The interrelationships and synergistic regulations of bioactive molecules play pivotal roles in physiological and pathological processes involved in the initiation and development of some diseases, such as cancer and neurodegenerative and cardiovascular diseases. Therefore, the simultaneous, accurate and timely detection of two bioactive molecules is crucial to explore their roles and pathological mechanisms in related diseases. Fluorescence imaging associated with small molecular probes has been widely used in the imaging of bioactive molecules in living cells and due to its excellent performances, including high sensitivity and selectivity, noninvasive properties, real-time and high spatial temporal resolution. Single organic molecule fluorescent probes have been successively developed to simultaneously monitor two biomolecules to uncover their synergistic relationships in living systems. Hence, in this review, we focus on summarizing the design strategies, classifications, and bioimaging applications of dual-response fluorescent probes over the past decade. Furthermore, future research directions in this field are proposed.

关键词： bioactive molecules     fluorescent probes     in living cells and in vivo     review    

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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-likecells enriched with tumor spheroids from a non-small cell lung cancer cell line

null

《医学前沿（英文）》 2013年 第7卷 第4期   页码 462-476 doi: 10.1007/s11684-013-0270-6

摘要：

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

关键词： drug resistance     cancer stem cell     checkpoint kinase 1 (CHK1)     PF-00477736     lung cancer     tumorigenicity    

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标题 作者 时间 类型 操作

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

期刊论文

Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging

null

期刊论文

Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

期刊论文

Recent advances of small-molecule fluorescent probes for detecting biological hydrogen sulfide

期刊论文

Genetic biosensors for small-molecule products: Design and applications in high-throughput screening

Qingzhuo Wang,Shuang-Yan Tang,Sheng Yang

期刊论文

Bright future of polymerizing small-molecule acceptors in realizing high performance all-polymer solar

Qi Chen1 , Cen Zhang1 , Lingwei Xue1,2 , Zhi-Guo Zhang1

期刊论文

Discovery of small molecule degraders for modulating cell cycle

期刊论文

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

期刊论文

Near-infrared benzodiazoles as small molecule environmentally-sensitive fluorophores

期刊论文

基于整合临床和动物实验的小分子筛选平台揭示经典方剂茵陈蒿汤治疗黄疸证显效状态下的活性化合物及潜在作用靶点

熊辉, 张爱华, 郭雅静, 周小航, 孙晖, 杨乐, 方衡, 闫广利, 王喜军

期刊论文

Design of nanocarriers for efficient cellular uptake and endosomal release of small molecule and nucleic

Vaibhav Mundra, Ram I. Mahato

期刊论文

Recent advances in small molecule fluorescent probes for simultaneous imaging of two bioactive molecules

Yongqing Zhou, Xin Wang, Wei Zhang, Bo Tang, Ping Li

期刊论文

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-likecells enriched with tumor spheroids from a non-small cell lung cancer cell line

null

期刊论文

饶燏：小分子靶向蛋白降解技术及应用（2022年12月15日）

2022年12月22日

会议视频

钟武：小分子抗新冠病毒药物的研究（2021年7月23日）

2021年10月23日

会议视频