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Experiences from a CRO Perspective in Leveraging Collaborative Medicinal Chemistry:Evolution of Hits to Optimized Tool Compounds for Novel Target Validation In Vivo

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Experiences from a CRO Perspective in Leveraging Collaborati...

2011年全国药物化学学术会议——药物的源头创新

作者： Richard soll s.vp wuxi apptec 288 Fute Zhong RoadFree TradeShanghai200131China

＜正＞The last number of years has witnessed the emergence of China as a vibrant center of drug discovery and an increasing reliance on global,externalized models of drug *** this presentation,perspectives and experie...

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Use of the DsI/Ponemah jacketed external telemetry system for ECG assessments in dog telemetry

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中国药理学与毒理学杂志 2013年第3期 601-602页

作者： WU Rui QU Lin-hai sue McPHERsON steve MAsON safety Pharmacology WuXi AppTec(Suzhou) Co.Ltd.

OBJECTIVE To demonstrate that the DsI /Ponemah Jet system(v5.00) can generate high quality ECG data with current methods,enabling cardiovascular function to be assessed in free moving dogs in their home *** Four male beagle dogs were used on this *** electrodes were placed on each animal and were connected to each JET *** JET device was then placed into a pocket of an externally worn animal jacket for each *** JET device transmits to a Bluetooth? *** Bluetooth? receiver can receive signals from up to 6 JET devices depending upon the device *** JET device can transmit data up to 10 meters with negligible interference and no cross-talk exists between *** animals underwent acclimatization to jackets prior to commencement of *** dog was placed into a pen and ECG measurements taken simultaneously using the DsI /Ponemah Jet *** were recorded for 1 hour pre-dose and continually for the following 23 hours under control conditions,then dosed with ascending doses of Moxifloxacin at intervals of 48 hours between each *** AND CONCLUsION Prolonged QT and QTcV(Van de Water's correction) interval was observed for animals dosed at 100 mg·kg-1 from 4-23 h *** QTcV effects(19% increase with 100 mg·kg-1 Moxifloxacin vs control).The DsI telemetry system performed well when testing the dog to the known pharmacological profile of *** sensitively and efficiently acquired ECG data from the beagle dogs and demonstrated the sensitivity of the system to detect test article induced QT *** allows a colony of dogs to be dedicated for toxicology and safety pharmacology *** DsI /ponemah JET system enables flexibility in study design and can be utilized on a range of study types to facilitate high quality ECGs and reduce the requirement for repeat dosing safety pharmacology *** data generated from this investigation demonstrate the DsI /ponemah JET system(v5.

关键词： ECG dog

DNA-encoded Library and DNA Compatible Chemistry

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DNA-encoded Library and DNA Compatible Chemistry

中国化学会第八届天然产物全合成青年学术研讨会

作者：彭宣嘉 wuxi apptec

The DNA-encoded chemical library（DECL） is a technology that has been considered as a powerful tool for small-molecule drug discovery in recent years.1 small molecules are synthesized and covalently conjugated to DNA tags using a split and pool strategy. And the DNA tag works as a "barcode" in DECL. After affinity selection, the binding library is amplified by polymerase chain reaction（PCR）, and the hit molecule’s structural information can be decoded from the attached DNA tags via high-throughput sequencing. In brief, DECL makes great innovation to search for potent hits or even lead candidates.2 It attracts great interest of academic institutions and pharmaceutical industries. DNA conjugated reactions with different functional groups are desired to rich the DECL diversity and chemical space.3 However, the types are limited as it requires stringent conditions: with water as co-solvent（above 20%）, mild conditions（pH 4-14, 4-90°C）, selectivity against DNA tags and so on.4 To date, although progress has been made for DNA compatible reactions applied to DECL. It is still minority compared to traditional organic reactions. so it is necessary to explore more DNA compatible reactions to expand the chemical space. wuxi apptec DEL platform committed to research on DNA compatible reactions. And great progress has been made at the monment. There are 45 kinds of DNA-compatible reactions have been developed in wuxi apptec DEL platform. Of which, 26 reactions have been used in the construction of compounds library. wuxi apptec DEL platform has constructed more than 270 compounds library including more than 90 billion small molecules. The platform also developed sveral innovative reactions, such as DNA compatible sulfonylation with sulfinic acids or sodium sulfinates, Pictet-spengler reaction, intermolecular Wittig reaction, click reaction for 1,5-triazole formation, suzuki coupling with potassium fluoroborate, oxidative amidation, conversions of diazonium salts and so on.

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Isatin hybrids and their anti-tuberculosis activity

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Chinese Chemical Letters 2017年第2期28卷 159-167页

作者： Zhi Xu shu Zhang Chuan Gao Jing Fan Feng Zhao Zao-sheng Lv Lian-shun Feng Wuhan University of science and Technology 430081 China Pony Testing International Group Wuhan 430034 China wuxi apptec Wuhan 430075 China Hengshui University Hengshui 053000 China synthetic and Functional Biomolecules Center Peking University Beijing 100871 China

Tuberculosis（TB） is one of the most common and even fatal infectious diseases known to *** of new cases are reported every year over the world,and one-third of the world＇s population is potentially infected with mycobacteria tuberculosis（MTB）.Research to develop novel anti-TB drugs led to the identification of several isatin-based antimycobacterial agents,among which a number of potential candidates displayed excellent antimycobacterial activity and were found to be free of *** review outlines the advances in the application of isatin hybrids as antimycobacterial agents and the critical aspects of design and structure-activity relationship of these derivatives.

关键词： Isatin hybrids Mycobacterium tuberculosis Quinolone structure-activity relationship Review

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software-aided detection and structural characterization of cyclic peptide metabolites in biological matrix by high-resolution mass spectrometry

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Journal of Pharmaceutical Analysis 2020年第3期10卷 240-246页

作者： Ming Yao Tingting Cai Eva Duchoslav Li Ma Xu Guo Mingshe Zhu Pharmaceutical Candidate Optimization Bristol-Myers SquibbPrincetonNJUSA XenoBiotic Labs WuXi AppTecNanjingChina sCIEX ConcordONL4K 4V8Canada MassDefect Technologies PrincetonNJUSA

Compared to their linear counterparts,cyclic peptides show better biological activities,such as antibacterial,immunosuppressive,and anti-tumor activities,and pharmaceutical properties due to their conformational ***,cyclic peptides could form numerous putative metabolites from potential hydrolytic cleavages and their fragments are very difficult to *** characteristics pose a great challenge when analyzing metabolites of cyclic peptides by mass *** study was to assess and apply a software-aided analytical workflow for the detection and structural characterization of cyclic peptide *** and atrial natriuretic peptide(ANP)as model cyclic peptides were incubated with trypsin/chymotrypsin and/or rat liver s9,followed by data acquisition using TripleTOF?*** full-scan Ms and Ms/Ms datasets were automatically processed through a combination of targeted and untargeted peak finding ***/Ms spectra of predicted metabolites were interrogated against putative metabolite sequences,in light of a,b,y and internal fragment *** resulting fragment assignments led to the confirmation and ranking of the metabolite sequences and identification of metabolic *** a result,29 metabolites with linear or cyclic structures were detected in the insulin incubation with the hydrolytic *** of twenty insulin metabolites were further determined,which were consistent with the hydrolytic sites of these *** the same manner,multiple metabolites of insulin and ANP formed in rat liver s9 incubation were detected and structurally characterized,some of which have not been previously *** results demonstrated the utility of software-aided data processing tool in detection and identification of cyclic peptide metabolites.

关键词： Atrial natriuretic peptide Metabolism of cyclic peptide High resolution mass spectrometry Insulin software-aided data processing

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

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Frontiers of Medicine 2013年第4期7卷 462-476页

作者： Douglas D.Fang Joan Cao Jitesh P.Jani Konstantinos Tsaparikos Alessandra Blasina Jill Kornmann Maruja E.Lira Jianying Wang Zuzana Jirout Justin Bingham Zhou Zhu Yin Gu Gerrit Los Zdenek Hostomsky Todd VanArsdale Oncology Research Unit PfizerInc.10777 Science Center DriveSan DiegoCA 92121USA wuxi apptec(shanghai)Co. Ltd.288 Fute Zhong RdWaigaoqiao Free Trade ZoneShanghai 200131China

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)*** 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 *** 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 ***,the CsC-like cells exhibited resistance to gemcitabine-induced ***,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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Use of the DsI/Ponemah jacketed external telemetry system for ECG assessments in dog telemetry

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Use of the DSI/Ponemah jacketed external telemetry system fo...

作者： WU Rui QU Lin-hai sue McPHERsON steve MAsON safety Pharmacology WuXi AppTec(Suzhou) Co.Ltd

OBJECTIVE To demonstrate that the DsI/Ponemah Jet system(v5.00) can generate high quality ECG data with current methods,enabling cardiovascular function to be assessed in free moving dogs in their home pens. METHODs Four male beagle dogs were used on this *** electrodes were placed on each animal and were connected to each JET *** JET device was then placed into a pocket of an externally worn animal jacket for each *** JET device transmits to a Bluetooth? *** Bluetooth? receiver can receive signals from up to 6 JET devices depending upon the device *** JET device can transmit data up to 10 meters with negligible interference and no cross-talk exists between *** animals underwent acclimatization to jackets prior to commencement of *** dog was placed into a pen and ECG measurements taken simultaneously using the DsI/Ponemah Jet *** were recorded for 1 hour pre-dose and continually for the following 23 hours under control conditions,then dosed with ascending doses of Moxifloxacin at intervals of 48 hours between each *** AND CONCLUsION Prolonged QT and QTcV(Van de Water s correction) interval was observed for animals dosed at 100 mg·kg~(-1) from 4-23 h *** QTcV effects(19%increase with 100 mg·kg~(-1) Moxifloxacin vs control).The DsI telemetry system performed well when testing the dog to the known pharmacological profile of *** sensitively and efficiently acquired ECG data from the beagle dogs and demonstrated the sensitivity of the system to detect test article induced QT changes. DsI allows a colony of dogs to be dedicated for toxicology and safety pharmacology *** DsI/ponemah JET system enables flexibility in study design and can be utilized on a range of study types to facilitate high quality ECGs and reduce the requirement for repeat dosing safety pharmacology *** data generated from this investigation demonstrate the DsI/ponemah JET system(

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Use of respiratory "head out" plethysmographs for evaluation of pulmonary function in rats

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Use of respiratory "head out" plethysmographs for evaluation...

作者： WU Rui QU Lin-hai sue MCPHERsON steve MAsON safety Pharmacology WuXi AppTec(Suzhou)Co.Ltd

To evaluate the use of respiratory "head out" plethysmographys for use as a respiratory function assessment tool in rats as part of the respiratory system assessment required under the ICH s7A ***(20 mg·kg~(-1) iv) and Theophylline(10 mg·kg~(-1)iv) were selected for use as reference compounds in this *** sprague- Dawley rats,approximately 7 -8 weeks of age and in the weight range 246 -303 g were selected as the test *** approximate one week acclimation period preceded the study,during which animals were pre-selected for the suitability by assessment of their ability to stay in the restraint chambers("head-out" plethysmographys) for a target of about 2.5 h-Any rat demonstrating excessive excitability or abnormal breathing patterns were removed from the *** the day of dosing, animals were placed in "head out" plethysmographs and allowed to acclimate to the chambers for at least 5 min prior to each data collection *** following the acclimation period,ventilatory parameters(tidal volume,respiratory rate,and derived respiratory minute volume(RMV) were measured for an approximate 15 min period predose,continuously for the following approximate 2.5 h,then for approximate 15 min at approximately 4 and 24 h *** obtained were consistent with the literature and based on the results of this study,this assay,using respiratory "head out" plethysmographys to assess respiratory function,is considered acceptable for use in Pulmonary assessments under the ICH guideline.

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Use of respiratory "head out" plethysmographs for evaluation of pulmonary function in rats

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Use of respiratory "head out" plethysmographs for evaluation...

2013年（第三届）中国药物毒理学年会暨药物非临床安全性评价研究论坛

作者： WU Rui QU Lin-hai sue MCPHERsON steve MAsON safety Pharmacology WuXi AppTec(Suzhou)Co.Ltd.

To evaluate the use of respiratory "head out" plethysmographys for use as a respiratory function assessment tool in rats as part of the respiratory system assessment required under the ICH s7A ***(20 mg ? kg iv) and Theophylline(10 mg·kg iv) were selected for use as reference compounds in this *** sprague-Dawley rats,approximately 7 -8 weeks of age and in the weight range 246 -303 g were selected as the test *** approximate one week acclimation period preceded the study,during which animals were pre-selected for the suitability by assessment of their ability to stay in the restraint chambers("head-out" plethysmographys) for a target of about 2.5 h-Any rat demonstrating excessive excitability or abnormal breathing patterns were removed from the *** the day of dosing, animals were placed in "head out" plethysmographs and allowed to acclimate to the chambers for at least 5 min prior to each data collection *** following the acclimation period,ventilatory parameters(tidal volume,respiratory rate,and derived respiratory minute volume(RMV) were measured for an approximate 15 min period predose,continuously for the following approximate 2.5 h,then for approximate 15 min at approximately 4 and 24 h *** obtained were consistent with the literature and based on the results of this study,this assay,using respiratory "head out" plethysmographys to assess respiratory function,is considered acceptable for use in Pulmonary assessments under the ICH guideline.

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