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Why 90%of clinical drug development fails and how to improve it?

Acta Pharmaceutica Sinica B 2022年第7期12卷 3049-3062页

作者： Duxin Sun Wei Gao Hongxiang Hu Simon Zhou Department of Pharmaceutical Sciences College of PharmacyUniversity of MichiganAnn ArborMI48109USA Translational development and Clinical Pharmacology Bristol Meyer Squibb CompanySummitNJ07920USA

Ninety percent of clinical drug development fails despite implementation of many successful strategies,which raised the question whether certain aspects in target validation and drug optimization are overlooked?Current drug optimization overly emphasizes potency/specificity using structure-activityrelationship(SAR)but overlooks tissue exposure/selectivity in disease/normal tissues using structure-tissue exposure/selectivity—relationship(STR),which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity.We propose structure-tissue exposure/selectivity—activity relationship(STAR)to improve drug optimization,which classifies drug candidates based on drug’s potency/selectivity,tissue exposure/selectivity,and required dose for balancing clinical efficacy/toxicity.ClassⅠdrugs have high specificity/potency and high tissue exposure/selectivity,which needs low dose to achieve superior clinical efficacy/safety with high success rate.ClassⅡdrugs have high specificity/potency and low tissue exposure/selectivity,which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated.ClassⅢdrugs have relatively low(adequate)specificity/potency but high tissue exposure/selectivity,which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked.ClassⅣdrugs have low specificity/potency and low tissue exposure/selectivity,which achieves inadequate efficacy/safety,and should be terminated early.STAR may improve drug optimization and clinical studies for the success of clinical drug development.

关键词： drug development drug optimization Clinical trial Structure-tissue exposure/selectivity relationship(STR) Structure-tissue exposure/selectivity—activity relationship(STAR)

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Cases studies of application of model-informed drug development in early phase clinical trials

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中国药理学与毒理学杂志 2023年第S1期37卷 39-40页

作者： ZHAO Wei Shandong University Department of Clinical Pharmacy School of Pharmaceutical SciencesJinan 250012China

Model-informed drug develop⁃ment(MIDD)is the application of a various math⁃ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho⁃physiology,and pharmacology can also be incor⁃porated into the model.MIDD is centered on knowledge and inferences generated from inte⁃grated models of the physicochemical character⁃istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop⁃ment,by improving clinical trial efficiency,opti⁃mizing dose and regimen and waive unneces⁃sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.

关键词： model-informed drug development drug development integration of information

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TCM-based new drug discovery and development in China

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Chinese Journal of Natural Medicines 2014年第4期12卷 241-250页

作者： WU Wan-Ying HOU Jin-Jun LONG Hua-Li YANG Wen-Zhi LIANG Jian GUO De-An Shanghai Research Center for Modernization of Traditional Chinese Medicine and National Engineering Laboratory for TCM Standardization Technology Shanghai Institute of Materia Medica Chinese Academy of Sciences

Over the past 30 years, China has significantly improved the drug development environment by establishing a series of policies for the regulation of new drug approval. The regulatory system for new drug evaluation and registration in China was gradually developed in accordance with international standards. The approval and registration of TCM in China became as strict as those of chemical drugs and biological products. In this review, TCM-based new drug discovery and development are introduced according to the TCM classification of nine categories.

关键词： China China Food and drug Administration(CFDA) Traditional Chinese Medicine Regulatory classification drug discovery drug development

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drug discovery and development targeting the life cycle of SARS-CoV-2

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Fundamental Research 2021年第2期1卷 151-165页

作者： Haixia Su Yechun Xu Hualiang Jiang CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicoChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

A newly emerged coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),belongs to the/β-coronavirus family and shows high similarities with SARS-CoV.O n March 11,2020,the World Health Organization(WHO)declared SARS-CoV-2 a global pandemic,and the disease was named the coronavirus disease 2019(COVID-19).The ongoing COVID-19 pandemic has caused over 46 million infections and over one million deaths worldwide,and the numbers are still increasing.Efficacious antiviral agents are urgently needed to combat this virus.The life cycle of SARS-CoV-2 mainly includes the viral attachment,membrane fusion,genomic replication,assembly and budding of virions.Accordingly,drug development against SARS-CoV-2 currently focuses on blocking spike protein binding to ACE2,inhibiting viral membrane fusion with host cells,and preventing the viral replication by targeting 3C-Iike protease,papain-like protease,RNA-dependent R N A polymerase as well as some host-cell proteins.In this review,the advances of drug development in these three major areas are elaborated.

关键词： SARS-CoV-2 COVID-19 drug development Antibody Inhibitors

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Human induced pluripotent stem cells derived hepatocytes:rising promise for disease modeling,drug development and cell therapy

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Protein & Cell 2012年第4期3卷 246-250页

作者： Fei Yi Guang-Hui Liu Juan Carlos Izpisua Belmonte Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCA 92037USA Center for Regenerative Medicine in Barcelona 08003 BarcelonaSpain National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.

关键词： induced pluripotent stem cells hepatocytes disease modeling drug development cell therapy

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Effects of marine compound xyloketal B on neuroprotection and potential drug development

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Journal of Coastal Life Medicine 2015年第6期3卷 429-432页

作者： Sammen Huang Wenliang Chen Jiyan Pang Zhong Pei Guan-Lei Wang Hong-Shuo Sun Department of Surgery Faculty of MedicineUniversity of TorontoTorontoOntarioCanada M5S 1A8 Department of Physiology Faculty of MedicineUniversity of TorontoTorontoOntarioCanada M5S 1A8 Department of Pharmacology and Toxicology Faculty of MedicineUniversity of TorontoTorontoOntarioCanada M5S 1A8 Department of Applied Chemistry School of Chemistry and Chemical EngineeringSun Yat-Sen UniversityGuangzhou 510275China Key Laboratory of Functional Moleculesfrom Oceanic Microorganisms(Sun Yat-Sen University) Department of Education of Guangdong Province510080China Department of Neurology The First Affiliated HospitalSun Yat-Sen UniversityGuangzhou 510080China Department of Pharmacology Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhou 510080China Institute of Medical Science Faculty of MedicineUniversity of TorontoTorontoOntarioCanada M5S 1A8

Coastal medicine is a promising field for research and drug development,because several natural products isolated from marine organisms have been found to be therapeutically useful in a clinical setting.In comparison to terrestrial products,the merit of marine compounds arises from the diversity in their chemical structure and unique bioactivity.A recently discovered marine compound,xyloketal B,displays neuroprotective and antioxidative effects in in-vitro and in-vivo experimental models.It elicits these beneficial effects through mitochondrial protection,free radical scavenging,reducing reactive oxygen species production and suppressing apoptotic signaling.In addition,unpublished data from our lab revealed that transient receptor potential melastatin 7 channel activity,implicated in a myriad of neurodegenerative diseases,was inhibited following xyloketal B administration.In this review,the therapeutic effect of xyloketal B will be evaluated based on existing evidence and its potential for drug development will be also discussed.

关键词： Marine compound Xyloketal B Neuroprotection Antioxidative drug development

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Research and development in drug innovation: reflections from the 2013 bioeconomy conference in China, lessons learned and future perspectives

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Acta Pharmaceutica Sinica B 2014年第2期4卷 112-119页

作者： Changxiao Liu Panayiotis P.Constantinides Yazhuo Li Tianjin Institute of Pharmaceutical Research Tianjin 300193China Biopharmaceutical and drug Delivery Consulting LLCGurneeIL 60031USA

The enormous progress biotechnology,bioinformatics and nanotechnology made in recent years provides opportunities and scientific framework for development of biomedicine and constitutes a paradigm shift in pharmaceutical R&D and drug innovation.By analyzing the data and related information at R&D level over the past decades,developmental tendency and R&D patterns were summarized.We found that a growing number of biologics in the pipeline of pharma companies with successful products already in the market though,small molecular entities have primarily dominated drug innovation.Additionally,small/medium size companies will continue to play a key role in the development of small molecule drugs and biologics in a multi-channel integrated process.More importantly,modern and effective R&D strategies in biomedicine development to predict and evaluate efficacy and/or safety of 21st century therapeutics are urgently needed.To face new challenges,developmental strategies were proposed,in terms of molecular targeted medicine,generic drugs,new drug delivery system and protein-based drugs.Under the current circumstances,interdisciplinary cooperation mode and policy related to drug innovation in China were deeply discussed as well.

关键词： Bioeconomy Biomedicine drug development Innovation Research and development Strategy and models

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Pancreatic ductal adenocarcinoma chemoresistance:From metabolism reprogramming to novel treatment

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Chinese Medical Journal 2024年第4期137卷 408-420页

作者： Jingcheng Zhang Yutong Wang Lejunzi Wang Lei You Taiping Zhang Department of General Surgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Peking Union Medical College Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Anaesthesia Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Clinical Immunology Centre Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

As pancreatic cancer(PC)is highly malignant,its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies.First-line chemotherapies for PC,according to current guidelines,include fluoropyrimidine-and gemcitabine-based regimens.Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC,especially those involving glycolysis and glutamine metabolism,are highly associated with chemoresistance.Additionally,lipid metabolism is a major factor in chemoresistance.However,emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance.This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.

关键词： Pancreatic cancer drug resistance drug development Signal transduction

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Bioactive peptides from scorpion venoms:therapeutic scaffolds and pharmacological tools

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Chinese Journal of Natural Medicines 2023年第1期21卷 19-35页

作者： Peter Muiruri Kamau ZHONG Jian YAO Bing LAI Ren LUO Lei Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesNational Resource Center for Non-Human PrimatesKunming Primate Research CenterNational Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Sino-African Joint Research Centerand Engineering Laboratory of PeptidesKunming Institute of ZoologyKunming 650107China Kunming College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Department of Reproductive Medicine Affiliated Jinling HospitalNanjing Medical UniversityNanjing 210002China Department of Gynecology Women’s Hospital of Nanjing Medical UniversityNanjing 210004China Center for Evolution and Conservation Biology Southern Marine Science and Engineering Guangdong LaboratoryGuangzhou 511458China

Evolution and natural selection have endowed animal venoms,including scorpion venoms,with a wide range of pharmacological properties.Consequently,scorpions,their venoms,and/or their body parts have been used since time immemorial in traditional medicines,especially in Africa and Asia.With respect to their pharmacological potential,bioactive peptides from scorpion venoms have become an important source of scientific research.With the rapid increase in the characterization of various components from scorpion venoms,a large number of peptides are identified with an aim of combating a myriad of emerging global health problems.Moreover,some scorpion venom-derived peptides have been established as potential scaffolds helpful for drug development.In this review,we summarize the promising scorpion venoms-derived peptides as drug candidates.Accordingly,we highlight the data and knowledge needed for continuous characterization and development of additional natural peptides from scorpion venoms,as potential drugs that can treat related diseases.

关键词： Scorpion venoms Scorpion venom-derived peptides Pharmacological properties drug development

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Potential medicinal plants involved in inhibiting 3CL^(pro) activity:A practical alternate approach to combating COVID-19

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Journal of Integrative Medicine 2022年第6期20卷 488-496页

作者： Fan Yang Xiao-lan Jiang Akash Tariq Sehrish Sadia Zeeshan Ahmed Jordi Sardans Muhammad Aleem Riaz Ullah Rainer W.Bussmann The Medical Center of General Practice Sichuan Academy of Medical Science and Sichuan Provincial People’s HospitalChengdu 610041Sichuan ProvinceChina Xinjiang Institute of Ecology and Geography Chinese Academy of SciencesUrumqi 830041Xinjiang Uygur Autonomous RegionChina Department of Biological Sciences University of Veterinary and Animal SciencesRavi CampusPattoki 55300Pakistan Consejo Superior de Investigaciones Científicas Global Ecology UnitCentre for Ecological Research and Forestry Applications-Consejo Superior de Investigaciones Científicas-Universitat Autònoma de BarcelonaBellaterra08193 BarcelonaCataloniaSpain Centre for Ecological Research and Forestry Applications Cerdanyola del Vallès 08193CataloniaSpain Department of Pharmacognosy College of PharmacyKing Saud UniversityRiyadh 11451Saudi Arabia Department of Ethnobotany Institute of Botanyllia State UniversityTbilisi 0105Georgia

At present,a variety of vaccines have been approved,and existing antiviral drugs are being tested to find an effective treatment for coronavirus disease 2019(COVID-19).However,no standardized treatment has yet been approved by the World Health Organization.The virally encoded chymotrypsin-like protease(3CL^(pro))from severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which facilitates the replication of SARS-CoV in the host cells,is one potential pharmacological target for the development of antiSARS drugs.Online search engines,such as Web of Science,Google Scholar,Scopus and PubMed,were used to retrieve data on the traditional uses of medicinal plants and their inhibitory effects against the SARS-CoV 3CL^(pro).Various pure compounds,including polyphenols,terpenoids,chalcones,alkaloids,biflavonoids,flavanones,anthraquinones and glycosides,have shown potent inhibition of SARS-CoV-2 3CL^(pro) activity with 50% inhibitory concentration(IC_(50))values ranging from 2-44μg/mL.Interestingly,most of these active compounds,including xanthoangelol E(isolated from Angelica keiskei),dieckol 1(isolated from Ecklonia cava),amentoflavone(isolated from Torreya nucifera),celastrol,pristimerin,tingenone and iguesterin(isolated from Tripterygium regelii),tannic acid(isolated from Camellia sinensis),and theaflavin-3,3’-digallate,3-isotheaflav1in-3 gallate and dihydrotanshinone I(isolated from Salvia miltiorrhiza),had IC_(50)values of less than 15μg/mL.Kinetic mechanistic studies of several active compounds revealed that their mode of inhibition was dose-dependent and competitive,with K_(i)values ranging from 2.4-43.8μmol/L.Given the significance of plant-based compounds and the many promising results obtained,there is still need to explore the phytochemical and mechanistic potentials of plants and their products.These medicinal plants could serve as an effective inexpensive nutraceutical for the general public to help manage COVID-19.

关键词： COVID-19 SARS-CoV-2 Coronavirus 3C proteases Medicinal plants Plant-derived compounds drug development

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