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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai Key Laboratory of Structure-Based drug Design and discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China department of Pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Structure and Anti-HIV Activity of Betulinic Acid Analogues

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Current Medical Science 2018年第3期38卷 387-397页

作者： Qiu-xia HUANG Hong-fei CHEN Xing-rui LUO Yin-xiang ZHANG Xu YAO Xing ZHENG University of South China Hengyang 421001 China Hunan Province Cooperative Innovation Center for Molecular target New drug Study Hengyang 421001 China

Firstly discovered in 1980s, human immunodeficiency virus （HIV） continues to affect more and more people. However, there is no effective drug available for the therapy of HIV infection. Betulinic acid existing in various medicinal herbs and fruits exhibits multiple biological effects, especially its outstanding anti-HIV activity, which has drawn the attentions of many pharmacists. Among the derivatives of betulinic acid, some compounds exhibited inhibitory activities at the nanomolar concentration, and have entered phase II clinical trials. This paper summarizes the current investigations on the anti-HIV activity of betulinic acid analogues, and provides valuable data for subsequent researches.

关键词： betulinic acid analogues HIV structural modification structure activity relationship

Development of SV2A Ligands for Epilepsy Treatment:A Review of Levetiracetam,Brivaracetam,and Padsevonil

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Neuroscience Bulletin 2024年第5期40卷 594-608页

作者： Peng-Peng Wu Bi-Rong Cao Fu-Yun Tian Zhao-Bing Gao Center for Neurological and Psychiatric Research and drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China University of Chinese Academy of Sciences Beijing100049China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan528400China

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug ***,there is an urgent need to develop alternative ***(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug *** it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains *** so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical *** review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.

关键词： Levetiracetam Epilepsy Antiseizure medications Synaptic vesicle protein 2A Brivaracetam Padsevonil

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

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Signal Transduction and targeted Therapy 2023年第1期8卷 13-37页

作者： Wenzhe Yi Ping Xiao Xiaochen Liu Zitong Zhao Xiangshi Sun Jue Wang Lei Zhou Guanru Wang Haiqiang Cao Dangge Wang Yaping Li State Key Laboratory of drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Yantai Key Laboratory of Nanomedicine&Advanced Preparations Yantai Institute of Materia MedicaYantai 264000China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264000China

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological *** metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal *** to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug *** the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target *** the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal *** then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and ***,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug *** expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

关键词： functional orthogonal breakthrough

Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4918-4933页

作者： Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou Lingang Laboratory Shanghai 200031China State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China drug discovery&Development Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent *** this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability ***,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL *** turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar *** importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL *** together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

关键词： Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide

Pharmacokinetics of H002, a novel S1PR_1 modulator, and its metabolites in rat blood using liquid chromatography–tandem mass spectrometry

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Acta Pharmaceutica Sinica B 2016年第6期6卷 576-583页

作者： Jiaqi Mi Manman Zhao Shu Yang Shuang Yang Jing Jin Xiaojian Wang Qiong Xiao Jinping Hu Yan Li department of drug Metabolism Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD StudyKey Laboratory of Active Substances Discovery and Drug Ability Evaluation State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College

A rapid and sensitive liquid chromatography–tandem mass spectrometry(LC–MS/MS) method was developed and validated for the simultaneous determination of H002 and its phosphorylated metabolite, H002-P and hydroxylated metabolite H002-M, in rat blood. H001, an analogue of H002, was used as the internal *** samples were prepared by simple protein precipitation. The analytes and internal standard were separated on a Zorbax SB-C18 column with a gradient mobile phase consisting of methanol and water containing 0.1% formic acid at a flow rate of 0.2 mL /min with an operating temperature of 20 1C. The detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization in multiple-reaction monitoring *** detection responses were obtained from 0.2–100 ng/mL for H002 and H002-M, while 0.5–100 ng/mL for H002-P. The intra- and inter-day precision(RSD%) was within 11.76%, with the accuracy(RE%) ranging from –9.84% to 9.12%. The analytes were shown to be stable during sample storage, preparation and analytic *** method was applied to determine the pharmacokinetics of H002 in rats, and a preliminary study showed that the pharmacokinetics of H002 correlated with its biological effect on peripheral blood lymphocytes.

关键词： S1P receptor S1PR1 modulator Sphingosine-1-phosphate S1P analogue Metabolite LC–MS/MS Pharmacokinetics Periphery blood lymphocyte

Mapping the Binding Site of P53 on UBC9 by NMR Spectroscopy

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Chinese Journal of Chemistry 2002年第10期20卷 937-943页

作者：林东海 department of Biochemistry The Hong Kong University of Science & Technology Hong Kong China Center for drug discovery and Design State Key Laboratory of Drug Research Shanghai Institute of Meteria Medica Shanghai Institutes of Biological Sciences Chinese Academy of Sciences Shanghai 200031 China

Human UBC9 is a member of the E2 family of proteins. However, instead of conjugating to ubiquitin, it conjugates to a ubiquitin homologue SUMO-1 (also known as UBL1, GMP1, SMTP3, PICT-1 and sentrin). The SUMO-1 conjugation pathway is very similar to that of ubiquitin with regard to the primary sequences of the ubiquitin activating enzymes (E1), the three-dimensional structures of the ubiquitin conjugating enzymes (E2), and the chemistry of the overall conjugation pathway. The interaction of p53 and UBC9, the E2 of the SUMO-1 pathway, has been studied by nuclear magnetic resonance spectroscopy. A peptide corresponding to the nuclear localization domain of p53 specifically interacts with UBC9 and this interaction is likely to be important for conjugation of p53 with SUMO-1. The largest chemical shift changes on UBC9 occur at residues 94 and 129-135. This region is adjacent to the active site and has significant dynamic behavior on the μs-ms and ps-ns timescales. Correlation of chemical shift changes and mobility of these residues further suggest the importance of these residues in substrate recognition.

关键词： NMR protein-peptide interaction SUMO-1 pathway E2 enzyme p53

Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits

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Signal Transduction and targeted Therapy 2023年第7期8卷 3427-3442页

作者： Liying Chen Yingwei Xu Heming Cheng Zhongxia Li Nanxi Lai Menghan Li Yeping Ruan Yang Zheng Fan Fei Cenglin Xu Jiao Ma Shuang Wang Yan Gu Feng Han Zhong Chen Yi Wang Institute of Pharmacology&Toxicology College of Pharmaceutical SciencesSchool of MedicineZhejiang UniversityHangzhouChina Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhouChina Zhejiang Rehabilitation Medical Center department The Third Affiliated HospitalZhejiang Chinese Medical UniversityHangzhouChina Key Laboratory of Cardiovascular&Cerebrovascular Medicine Drug Target and Drug Discovery CenterSchool of PharmacyNanjing Medical UniversityNanjingChina

Temporal lobe epilepsy(TLE),one common type of medically refractory epilepsy,is accompanied with altered adult-born dentate granule cells(abDGCs).However,the causal role of abDGCs in recurrent seizures of TLE is not fully ***,taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner.

关键词： epilepsy seizures maintain

Alisol B 23-acetate-induced HepG2 hepatoma cell death through mTOR signaling-initiated G_1 cell cycle arrest and apoptosis: A quantitative proteomic study

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Chinese Journal of Cancer Research 2019年第2期31卷 375-388页

作者： Ji Xia Qiang Luo Shengbin Huang Fuquan Jiang Lin Wang Guanghui Wang Jingjing Xie Jie Liu Yang Xu School of Pharmaceutical Sciences Fujian Provincial Key Laboratory of Innovative Drug Target Research Xiamen University department of Oncology Zhongshan Hospital of Xiamen University Institute of Gastrointestinal Oncology Medical College of Xiamen University

Objective: The present study aimed to investigate the molecular events in alisol B 23-acetate(ABA) cytotoxic activity against a liver cancer cell ***: First, we employed a quantitative proteomics approach based on stable isotope labeling by amino acids in cell culture(SILAC) to identify the different proteins expressed in HepG2 liver cancer cells upon exposure to ABA. Next, bioinformatics analyses through DAVID and STRING on-line tools were used to predict the pathways involved. Finally, we applied functional validation including cell cycle analysis and Western blotting for apoptosis and mTOR pathway-related proteins to confirm the bioinformatics ***: We identified 330 different proteins with the SILAC-based quantitative proteomics approach. The bioinformatics analysis and the functional validation revealed that the mTOR pathway, ribosome biogenesis, cell cycle, and apoptosis pathways were differentially regulated by ABA. G1 cell cycle arrest, apoptosis and mTOR inhibition were ***: ABA, a potential mTOR inhibitor, induces the disruption of ribosomal biogenesis. It also affects the mTOR-MRP axis to cause G1 cell cycle arrest and finally leads to cancer cell apoptosis.

关键词： Alisol B 23-acetate apoptosis cell cycle mTOR ribosome proteins

Radical coupling of β-ketoesters and amides promoted by Brønsted/ Lewis acids

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Green Synthesis and Catalysis 2020年第1期1卷 70-74页

作者： Joshua L.Zhu Stephen W.Laws Michael J.Rourke Karl A.Scheidt department of Chemistry Center for Molecular Innovation and Drug DiscoveryNorthwestern UniversityEvanstonIL 60208United States

Recent advances in photocatalysis have enabled radical methods with complementary chemoselectivity to established two electron bond forming *** this radical strategy has previously been limited to substrates with favorable redox potentials,Brønsted/Lewis acid activation has emerged as a means of facilitating otherwise difficult *** report herein our investigations into the Lewis acid-promoted redox activation ofβ-ketocarbonyls in a model photocatalytic radical alkylation *** evaluation of substrates and reactions conditions was achieved by high throughput experimentation using 96-well plate photoreactors.

关键词： Photochemistry Lewis acid Catalysis Alkylation Radicals