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Targeted protein degradation: current molecular targets, localization, and strategies 靶向蛋白质降解：当前的分子靶点、定位和策略
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-12 DOI: 10.1016/j.drudis.2024.104178
Dimanthi Pliatsika, Cindy Blatter, Rainer Riedl
{"title":"Targeted protein degradation: current molecular targets, localization, and strategies","authors":"Dimanthi Pliatsika,&nbsp;Cindy Blatter,&nbsp;Rainer Riedl","doi":"10.1016/j.drudis.2024.104178","DOIUrl":"10.1016/j.drudis.2024.104178","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has revolutionized drug discovery by selectively eliminating specific proteins within and outside the cellular context. Over the past two decades, TPD has expanded its focus beyond well-established targets, exploring diverse proteins beyond cancer-related ones. This evolution extends the potential of TPD to various diseases. Notably, TPD can target proteins at demanding locations, such as the extracellular matrix (ECM) and cellular membranes, presenting both opportunities and challenges for future research. In this review, we comprehensively examine the exciting opportunities in the burgeoning field of TPD, highlighting different targets, their cellular environment, and innovative strategies for modern drug discovery.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104178"},"PeriodicalIF":6.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical strategies with antibody–drug conjugates as potential modifications for virotherapy 将抗体药物共轭物作为病毒疗法潜在改良剂的临床策略
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-11 DOI: 10.1016/j.drudis.2024.104165
Zi-Xian Liao , Po-Hsiang Huang , Shan-hui Hsu , Hsiung-Hao Chang , Chi-Heng Chang , S.-Ja Tseng
{"title":"Clinical strategies with antibody–drug conjugates as potential modifications for virotherapy","authors":"Zi-Xian Liao ,&nbsp;Po-Hsiang Huang ,&nbsp;Shan-hui Hsu ,&nbsp;Hsiung-Hao Chang ,&nbsp;Chi-Heng Chang ,&nbsp;S.-Ja Tseng","doi":"10.1016/j.drudis.2024.104165","DOIUrl":"10.1016/j.drudis.2024.104165","url":null,"abstract":"<div><p>The ability to selectively target cancer cells makes antibody–drug conjugates (ADCs) promising therapeutic options. They have been tested in clinical trials as a vehicle for tumor-specific delivery of cytotoxic payloads for a range of cancers. However, systemic administration of oncolytic virotherapy is challenging, because only a small portion of injected viruses reach the target. Despite the approval of higher viral doses, most viruses still end up in the liver, potentially causing toxicity in that organ. Integrating ADCs with virotherapy in the form of antibody–virus conjugates or virus–drug conjugates can potentially overcome these challenges and improve therapeutic outcomes.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104165"},"PeriodicalIF":6.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Embryonic and larval zebrafish models for the discovery of new bioactive compounds against tuberculosis 用于发现抗结核新生物活性化合物的胚胎和幼体斑马鱼模型。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-07 DOI: 10.1016/j.drudis.2024.104163
Stella S. Antunes , Gabriel Forn-Cuní , Nelilma C. Romeiro , Herman P. Spaink , Fons J. Verbeek , Michelle F. Muzitano
{"title":"Embryonic and larval zebrafish models for the discovery of new bioactive compounds against tuberculosis","authors":"Stella S. Antunes ,&nbsp;Gabriel Forn-Cuní ,&nbsp;Nelilma C. Romeiro ,&nbsp;Herman P. Spaink ,&nbsp;Fons J. Verbeek ,&nbsp;Michelle F. Muzitano","doi":"10.1016/j.drudis.2024.104163","DOIUrl":"10.1016/j.drudis.2024.104163","url":null,"abstract":"<div><p>Tuberculosis (TB) is a world health challenge the treatment of which is impacted by the rise of drug-resistant strains. Thus, there is an urgent need for new antitubercular compounds and novel approaches to improve current TB therapy. The zebrafish animal model has become increasingly relevant as an experimental system. It has proven particularly useful during early development for aiding TB drug discovery, supporting both the discovery of new insights into mycobacterial pathogenesis and the evaluation of therapeutical toxicity and efficacy <em>in vivo</em>. In this review, we summarize the past two decades of zebrafish–<em>Mycobacterium marinum</em> research and discuss its contribution to the field of bioactive antituberculosis therapy development.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104163"},"PeriodicalIF":6.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators P-糖蛋白（P-gp）驱动的癌症耐药性：生物学概况、非编码 RNA、药物和纳米调节剂。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-07 DOI: 10.1016/j.drudis.2024.104161
Yang Guo , Milad Ashrafizadeh , Murtaza M. Tambuwala , Jun Ren , Gorka Orive , Guiping Yu
{"title":"P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators","authors":"Yang Guo ,&nbsp;Milad Ashrafizadeh ,&nbsp;Murtaza M. Tambuwala ,&nbsp;Jun Ren ,&nbsp;Gorka Orive ,&nbsp;Guiping Yu","doi":"10.1016/j.drudis.2024.104161","DOIUrl":"10.1016/j.drudis.2024.104161","url":null,"abstract":"<div><p>Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)–Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104161"},"PeriodicalIF":6.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Collaborative GSK–University of Strathclyde doctoral research and training programmes: Transforming approaches to industry–academia engagement 葛兰素史克公司与斯特拉思克莱德大学的合作博士研究和培训计划：转变产学合作方式。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-07 DOI: 10.1016/j.drudis.2024.104162
Laura C. Paterson , Philip G. Humphreys , Henry A. Kelly , William J. Kerr
{"title":"Collaborative GSK–University of Strathclyde doctoral research and training programmes: Transforming approaches to industry–academia engagement","authors":"Laura C. Paterson ,&nbsp;Philip G. Humphreys ,&nbsp;Henry A. Kelly ,&nbsp;William J. Kerr","doi":"10.1016/j.drudis.2024.104162","DOIUrl":"10.1016/j.drudis.2024.104162","url":null,"abstract":"<div><p>A global biopharma company, GSK, and the University of Strathclyde have developed an expansive and transformative research and training partnership originating in chemistry-aligned disciplines, with subsequent extensive expansion across further areas of the company. This has opened unique approaches for the delivery of collaborative research innovations while also enhancing the professional development and learning of GSK personnel, in addition to other embedded researchers and collaborating scientists, on a pathway towards more rapid and efficient discovery of new medicines.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104162"},"PeriodicalIF":6.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1359644624002873/pdfft?md5=684af4e4b7ff730912e2bd4dc063439b&pid=1-s2.0-S1359644624002873-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The pharmaceutical productivity gap – Incremental decline in R&D efficiency despite transient improvements 制药生产率差距--研发效率虽有短暂提高，但仍在逐步下降。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-05 DOI: 10.1016/j.drudis.2024.104160
Kenneth D.S. Fernald, Philipp C. Förster, Eric Claassen, Linda H.M. van de Burgwal
{"title":"The pharmaceutical productivity gap – Incremental decline in R&D efficiency despite transient improvements","authors":"Kenneth D.S. Fernald,&nbsp;Philipp C. Förster,&nbsp;Eric Claassen,&nbsp;Linda H.M. van de Burgwal","doi":"10.1016/j.drudis.2024.104160","DOIUrl":"10.1016/j.drudis.2024.104160","url":null,"abstract":"<div><p>Rising research and development costs, currently exceeding $3.5 billion per novel drug, reflect a five-decade decline in pharmaceutical R&amp;D efficiency. While recent reports suggest a potential turnaround, this review offers a systems-level analysis to explore whether this marks a structural shift or transient reversal. We analyzed financial data from the 200 largest pharmaceutical firms, novel drug approvals, and more than 80 000 clinical trials between 2012 and 2023. Our analysis revealed that despite recent stabilization, the pharmaceutical industry continues to face challenges, particularly due to elevated late-stage clinical attrition, suggesting that a sustained turnaround in R&amp;D efficiency remains elusive.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104160"},"PeriodicalIF":6.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S135964462400285X/pdfft?md5=6183df0c7f5f5378cd212c69c2ae5b5f&pid=1-s2.0-S135964462400285X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neurotrophin peptidomimetics for the treatment of neurodegenerative diseases 用于治疗神经退行性疾病的神经营养素肽模拟物。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-02 DOI: 10.1016/j.drudis.2024.104156
Dev Madhubala , Rosy Mahato , Mojibur R. Khan , Asis Bala , Ashis K. Mukherjee
{"title":"Neurotrophin peptidomimetics for the treatment of neurodegenerative diseases","authors":"Dev Madhubala ,&nbsp;Rosy Mahato ,&nbsp;Mojibur R. Khan ,&nbsp;Asis Bala ,&nbsp;Ashis K. Mukherjee","doi":"10.1016/j.drudis.2024.104156","DOIUrl":"10.1016/j.drudis.2024.104156","url":null,"abstract":"<div><p>Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, play an essential role in the survival of neurons. However, incorporating better features can increase their therapeutic efficacy in neurodegenerative diseases (NDs). Peptidomimetics, which mimic these neurotrophins, show potential for treating NDs. This study emphasizes the use of peptidomimetics from neurotrophins for treating NDs and their benefits. By improving bioavailability and stability, these molecules can completely transform the therapy for NDs. This in-depth review guides researchers and pharmaceutical developers, providing insight into the changing field of neurodegenerative medicine.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104156"},"PeriodicalIF":6.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy 用小分子抑制剂靶向真核细胞延伸因子 2 激酶（eEF2K）治疗癌症。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-08-28 DOI: 10.1016/j.drudis.2024.104155
Huiping Wang , Wenke Jin , Zixiang Li , Chuanxin Guo , Lan Zhang , Leilei Fu
{"title":"Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy","authors":"Huiping Wang ,&nbsp;Wenke Jin ,&nbsp;Zixiang Li ,&nbsp;Chuanxin Guo ,&nbsp;Lan Zhang ,&nbsp;Leilei Fu","doi":"10.1016/j.drudis.2024.104155","DOIUrl":"10.1016/j.drudis.2024.104155","url":null,"abstract":"<div><p>Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the α-kinase family that is activated by calcium/calmodulin. Of note, eEF2K is crucial for regulating translation and is often highly overexpressed in malignant cells. Therefore in this review, we summarize the molecular structure of eEF2K and its oncogenic roles in cancer. Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 10","pages":"Article 104155"},"PeriodicalIF":6.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanical network motifs as targets for mechanomedicine 作为机械医学目标的机械网络图案。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-08-23 DOI: 10.1016/j.drudis.2024.104145
Mengnan Lu , Zhao Xu , Feng Xu , Chunyan Yin , Hui Guo , Bo Cheng
{"title":"Mechanical network motifs as targets for mechanomedicine","authors":"Mengnan Lu ,&nbsp;Zhao Xu ,&nbsp;Feng Xu ,&nbsp;Chunyan Yin ,&nbsp;Hui Guo ,&nbsp;Bo Cheng","doi":"10.1016/j.drudis.2024.104145","DOIUrl":"10.1016/j.drudis.2024.104145","url":null,"abstract":"<div><p>The identification and analysis of network motifs has been widely used in the functional analysis of signaling components, disease discovery and other fields. The positive feedback loop (PFL) is a simple but important network motif. The formation of a PFL is regulated by mechanical cues such as substrate stiffness, fiber stretching and cell compression in the cell microenvironment. Here, we propose a new term, ‘mechanical PFL’, and analyze the mechanisms of mechanical PFLs at molecular, subcellular and cellular scales. More and more therapies are being targeted against mechanosignaling pathways at the experimental and preclinical stages, and exploring mechanical PFLs as potential mechanomedicine targets could be a new direction for disease treatment.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 10","pages":"Article 104145"},"PeriodicalIF":6.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chemical coverage of human biological pathways 人类生物途径的化学覆盖范围。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-08-22 DOI: 10.1016/j.drudis.2024.104144
Haejin Angela Kwak , Lihua Liu , Claudia Tredup , Sandra Röhm , Panagiotis Prinos , Jark Böttcher , Matthieu Schapira
{"title":"Chemical coverage of human biological pathways","authors":"Haejin Angela Kwak ,&nbsp;Lihua Liu ,&nbsp;Claudia Tredup ,&nbsp;Sandra Röhm ,&nbsp;Panagiotis Prinos ,&nbsp;Jark Böttcher ,&nbsp;Matthieu Schapira","doi":"10.1016/j.drudis.2024.104144","DOIUrl":"10.1016/j.drudis.2024.104144","url":null,"abstract":"<div><p>Chemical probes and chemogenomic compounds are valuable tools to link gene to phenotype, explore human biology, and uncover novel targets for precision medicine. The mission of the Target 2035 initiative is to discover chemical tools for all human proteins by the year 2035. Here, we draw a landscape of the current chemical coverage of human biological pathways. Although available chemical tools target only 3% of the human proteome, they already cover 53% of human biological pathways and represent a versatile toolkit to dissect a vast portion of human biology. Pathways targeted by existing drugs may be enriched in unknown but valid drug targets and could be prioritized in future Target 2035 efforts.</p></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 10","pages":"Article 104144"},"PeriodicalIF":6.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1359644624002691/pdfft?md5=fd391cdfa8c932ff2a0d499beadcdad0&pid=1-s2.0-S1359644624002691-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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