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

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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)

Global trends in diabetic eye disease research from 2012 to 2021

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Neural Regeneration Research 2024年第10期19卷 2310-2320页

作者： Yuan Yuan Shangli Ji Yali Song Zhaodi Che Lu Xiao Shibo Tang Jia Xiao Aier School of Ophthalmology Central South UniversityChangshaHunan ProvinceChina Changsha Aier Eye Hospital ChangshaHunan ProvinceChina Aier Eye Institute ChangshaHunan ProvinceChina Department of Metabolic and Bariatric Surgery The First Affiliated Hospital of Jinan UniversityGuangzhouGuangdong ProvinceChina

Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and Pub Med databases, all global registered clinical trials in the Clinical Trials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority(89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema(9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development(58.19%). Approximately half of the trials(49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic(40 out of 1830;2.19%) and diabetic eye disease(3 out of 1830;0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.

关键词： clinical trials diabetic cataracts diabetic eye disease diabetic glaucoma diabetic macular edema diabetic retinopathy drug development global research publication research grant

Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping Liu Yajing Li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China School of Life Sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： Liver fibrosis Epigenetics regulation DNA methylation Histone acetylation Histone methylation mRNA methylation Non-coding RNA drug development

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

Strategies for translating proteomics discoveries into drug discovery for dementia

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Neural Regeneration Research 2024年第1期19卷 132-139页

作者： Aditi Halder Eleanor Drummond School of Medical Sciences and Brain&Mind Center University of SydneyNSWSydneyAustralia Department of Aged Care Prince of Wales HospitalSydneyNSWAustralia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

关键词： Alzheimer's disease biomarkers drug development drug discovery druggability frontotemporal dementia interactome proteomics tau tauopathies therapeutics

Oligomerization of drug transporters:Forms,functions,and mechanisms

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1924-1938页

作者： Chunxu Ni Mei Hong College of Life Sciences South China Agricultural UniversityGuangzhou 510642China Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms South China Agricultural UniversityGuangzhou 510642China

drug transporters are essential players in the transmembrane transport of a wide variety of clinical drugs.The broad substrate spectra and versatile distribution pattern of these membrane proteins infer their pharmacological and clinical significance.With our accumulating knowledge on the three-dimensional structure of drug transporters,their oligomerization status has become a topic of intense study due to the possible functional roles carried out by such kind of post-translational modification(PTM).In-depth studies of oligomeric complexes formed among drug transporters as well as their interactions with other regulatory proteins can help us better understand the regulatory mechanisms of these membrane proteins,provide clues for the development of novel drugs,and improve the therapeutic efficacy.In this review,we describe different oligomerization forms as well as their structural basis of major drug transporters in the ATP-binding cassette and solute carrier superfamilies,summarize our current knowledge on the influence of oligomerization for protein expression level and transport function of these membrane proteins,and discuss the regulatory mechanisms of oligomerization.Finally,we highlight the challenges associated with the current oligomerization studies and propose some thoughts on the pharmaceutical application of this important drug transporter PTM.

关键词： drug development drug transporters Oligomerization Protein expression Protein–protein interaction Regulatory mechanism Structural basis Transport function

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

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

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