The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.
{"title":"Advances in molecular glues: exploring chemical space and design principles for targeted protein degradation","authors":"Hemant Kumar S , Muthukumaran Venkatachalapathy , Ramesh Sistla , Vasanthanathan Poongavanam","doi":"10.1016/j.drudis.2024.104205","DOIUrl":"10.1016/j.drudis.2024.104205","url":null,"abstract":"<div><div>The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104205"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405788","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}
Pub Date : 2024-10-29DOI: 10.1016/j.drudis.2024.104217
Weronika Bagrowska, Angelika Karasewicz, Artur Góra
The main function of acetylcholinesterase (AChE) is to regulate the levels of one of the most important neurotransmitters: acetylcholine. This makes AChE an ideal molecular target for the treatment of neurodegenerative diseases and dementia (such as Alzheimer’s disease), as well as for the neutralisation of natural toxins (e.g., venom peptides) and chemical warfare agents. The significance of AChE inhibitors in slowing the progression of dementia, as well as the role of reactivators in treating poisoned individuals, is reflected in several co-crystallised complexes deposited in the Protein Data Bank. In this study, we analysed all deposited AChE–small-molecule complexes to gain insights into compound binding and to provide guidance for the future design of therapeutic drugs and new antidotes.
乙酰胆碱酯酶（AChE）的主要功能是调节最重要的神经递质之一乙酰胆碱的水平。这使得乙酰胆碱酯酶成为治疗神经退行性疾病和痴呆症（如阿尔茨海默病）以及中和天然毒素（如毒液肽）和化学战剂的理想分子靶点。AChE 抑制剂在延缓痴呆症进展方面的重要作用，以及再激活剂在治疗中毒者方面的作用，都反映在蛋白质数据库（Protein Data Bank）中的几种共晶体复合物中。在这项研究中，我们分析了所有保存的 AChE-小分子复合物，以深入了解化合物的结合情况，为今后设计治疗药物和新的解毒剂提供指导。
{"title":"Comprehensive analysis of acetylcholinesterase inhibitor and reactivator complexes: implications for drug design and antidote development","authors":"Weronika Bagrowska, Angelika Karasewicz, Artur Góra","doi":"10.1016/j.drudis.2024.104217","DOIUrl":"10.1016/j.drudis.2024.104217","url":null,"abstract":"<div><div>The main function of acetylcholinesterase (AChE) is to regulate the levels of one of the most important neurotransmitters: acetylcholine. This makes AChE an ideal molecular target for the treatment of neurodegenerative diseases and dementia (such as Alzheimer’s disease), as well as for the neutralisation of natural toxins (e.g., venom peptides) and chemical warfare agents. The significance of AChE inhibitors in slowing the progression of dementia, as well as the role of reactivators in treating poisoned individuals, is reflected in several co-crystallised complexes deposited in the Protein Data Bank. In this study, we analysed all deposited AChE–small-molecule complexes to gain insights into compound binding and to provide guidance for the future design of therapeutic drugs and new antidotes.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104217"},"PeriodicalIF":6.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542503","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}
Pub Date : 2024-10-29DOI: 10.1016/j.drudis.2024.104220
Ruilin Wu , Hong Zhu , Qiaojun He , Tao Yuan , Bo Yang
Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered ‘untargetable’. Although specific KRASG12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.
{"title":"Metabolic reprogramming in KRAS-mutant cancers: Proven targetable vulnerabilities and potential therapeutic strategies","authors":"Ruilin Wu , Hong Zhu , Qiaojun He , Tao Yuan , Bo Yang","doi":"10.1016/j.drudis.2024.104220","DOIUrl":"10.1016/j.drudis.2024.104220","url":null,"abstract":"<div><div><em>Kras</em> (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered ‘untargetable’. Although specific KRAS<sup>G12C</sup> inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104220"},"PeriodicalIF":6.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556738","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}
Pub Date : 2024-10-29DOI: 10.1016/j.drudis.2024.104219
Taskeen F. Docrat , Ali O.E. Eltahir , Ahmed A. Hussein , Jeanine.L. Marnewick
Glioblastoma, the most aggressive brain cancer, is challenging to treat owing to the difficulty of crossing the blood–brain barrier, high recurrence rates and significant mortality. This review highlights the potential of green synthesis methods in developing metal nanoparticles (MNPs) as a sustainable solution for drug delivery systems targeting glioblastoma. We explore the unique properties and modes of action of MNPs synthesised through eco-friendly processes by focusing on their bioavailability and precision in brain targeting, and discuss the potential of MNPs to target glioblastoma at the molecular level. Integrating green synthesis into cancer therapeutics represents a novel paradigm shift towards treatments with higher efficacy and lower environmental impact, offering hope in the fight against glioblastoma.
{"title":"Green synthesis of metal nanocarriers: A perspective for targeting glioblastoma","authors":"Taskeen F. Docrat , Ali O.E. Eltahir , Ahmed A. Hussein , Jeanine.L. Marnewick","doi":"10.1016/j.drudis.2024.104219","DOIUrl":"10.1016/j.drudis.2024.104219","url":null,"abstract":"<div><div>Glioblastoma, the most aggressive brain cancer, is challenging to treat owing to the difficulty of crossing the blood–brain barrier, high recurrence rates and significant mortality. This review highlights the potential of green synthesis methods in developing metal nanoparticles (MNPs) as a sustainable solution for drug delivery systems targeting glioblastoma. We explore the unique properties and modes of action of MNPs synthesised through eco-friendly processes by focusing on their bioavailability and precision in brain targeting, and discuss the potential of MNPs to target glioblastoma at the molecular level. Integrating green synthesis into cancer therapeutics represents a novel paradigm shift towards treatments with higher efficacy and lower environmental impact, offering hope in the fight against glioblastoma.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104219"},"PeriodicalIF":6.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542504","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}
Natural products (NPs) are privileged structures interacting with biomacromolecular targets and exhibiting biological effects important for human health. In this review, we have presented NP-inspired strategic innovations that are promising for addressing preclinical and clinical challenges. An analysis of ‘molecule-to-medicinal’ properties for improvement of P3 and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles has been illustrated. The strategies include chemical evolution through knowledge of structure–medicinal properties, truncation of NPs to avoid molecular obesity, pseudo-NPs, selection of common structural features of NPs, medicinophore installation, scaffold hopping, and induced proximity. Molecule-to-medicinal property analysis can guide the development of ‘nature-to-new’ chemical therapeutics. Coupled with scientific advances and innovations in instrumentation, these strategies hold great potential for enhancing drug design and discovery.
{"title":"How to nurture natural products to create new therapeutics: Strategic innovations and molecule-to-medicinal insights into therapeutic advancements","authors":"Ayan Acharya, Mithilesh Nagpure, Nibedita Roy, Vaibhav Gupta, Soumyadeep Patranabis, Sankar K. Guchhait","doi":"10.1016/j.drudis.2024.104221","DOIUrl":"10.1016/j.drudis.2024.104221","url":null,"abstract":"<div><div>Natural products (NPs) are privileged structures interacting with biomacromolecular targets and exhibiting biological effects important for human health. In this review, we have presented NP-inspired strategic innovations that are promising for addressing preclinical and clinical challenges. An analysis of ‘molecule-to-medicinal’ properties for improvement of P3 and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles has been illustrated. The strategies include chemical evolution through knowledge of structure–medicinal properties, truncation of NPs to avoid molecular obesity, pseudo-NPs, selection of common structural features of NPs, medicinophore installation, scaffold hopping, and induced proximity. Molecule-to-medicinal property analysis can guide the development of ‘nature-to-new’ chemical therapeutics. Coupled with scientific advances and innovations in instrumentation, these strategies hold great potential for enhancing drug design and discovery.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104221"},"PeriodicalIF":6.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556737","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}
Pub Date : 2024-10-22DOI: 10.1016/j.drudis.2024.104211
Ben Sidders
{"title":"Elevating life science R&D success with AI: a framework","authors":"Ben Sidders","doi":"10.1016/j.drudis.2024.104211","DOIUrl":"10.1016/j.drudis.2024.104211","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104211"},"PeriodicalIF":6.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491946","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}
Developing new drugs from marketed ones is a well-established and successful approach in drug discovery. We offer a unified view of this field, focusing on the new chemical aspects of the involved approaches: (a) chemical transformation of the original drugs (late-stage modifications, molecular editing), (b) prodrug strategies, and (c) repurposing as a tool to develop new hits/leads. Special focus is placed on the molecular structure of the drugs and their synthetic feasibility. The combination of experimental advances and new computational approaches, including artificial intelligence methods, paves the way for the evolution of the drugs from drugs concept.
{"title":"Drugs from drugs: New chemical insights into a mature concept","authors":"Eloy Lozano Baró , Federica Catti , Carolina Estarellas , Ouldouz Ghashghaei , Rodolfo Lavilla","doi":"10.1016/j.drudis.2024.104212","DOIUrl":"10.1016/j.drudis.2024.104212","url":null,"abstract":"<div><div>Developing new drugs from marketed ones is a well-established and successful approach in drug discovery. We offer a unified view of this field, focusing on the new chemical aspects of the involved approaches: (a) chemical transformation of the original drugs (late-stage modifications, molecular editing), (b) prodrug strategies, and (c) repurposing as a tool to develop new hits/leads. Special focus is placed on the molecular structure of the drugs and their synthetic feasibility. The combination of experimental advances and new computational approaches, including artificial intelligence methods, paves the way for the evolution of the drugs from drugs concept.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104212"},"PeriodicalIF":6.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491945","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}
Pub Date : 2024-10-18DOI: 10.1016/j.drudis.2024.104215
Ting Xu , Shuang Wang , Tingting Ma , Yawen Dong , Charles R. Ashby Jr , Ge-Fei Hao
Accurately identifying biological targets is crucial for advancing treatment options. Essential genes, vital for cell or organism survival, hold promise as potential drug targets in disease treatment. Although many studies have sought to identify essential genes as therapeutic targets in medicine and bioinformatics, systematic reviews on their relationship with drug targets are relatively rare. This work presents a comprehensive analysis to aid in identifying essential genes as potential targets for drug discovery, encompassing their relevance, identification methods, successful case studies, and challenges. This work will facilitate the identification of essential genes as therapeutic targets, thereby boosting new drug development.
{"title":"The identification of essential cellular genes is critical for validating drug targets","authors":"Ting Xu , Shuang Wang , Tingting Ma , Yawen Dong , Charles R. Ashby Jr , Ge-Fei Hao","doi":"10.1016/j.drudis.2024.104215","DOIUrl":"10.1016/j.drudis.2024.104215","url":null,"abstract":"<div><div>Accurately identifying biological targets is crucial for advancing treatment options. Essential genes, vital for cell or organism survival, hold promise as potential drug targets in disease treatment. Although many studies have sought to identify essential genes as therapeutic targets in medicine and bioinformatics, systematic reviews on their relationship with drug targets are relatively rare. This work presents a comprehensive analysis to aid in identifying essential genes as potential targets for drug discovery, encompassing their relevance, identification methods, successful case studies, and challenges. This work will facilitate the identification of essential genes as therapeutic targets, thereby boosting new drug development.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104215"},"PeriodicalIF":6.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454529","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}
Pub Date : 2024-10-18DOI: 10.1016/j.drudis.2024.104214
Andrejs Sitovs , Valentyn Mohylyuk
Ex vivo drug permeability testing across gastrointestinal (GI) membranes is crucial in drug discovery and oral drug delivery. It is a reliable method for drugs with good solubility, but it poses challenges for poorly soluble drugs, which are common in development pipelines today. Although enabling formulations increase the apparent solubility in the GI compartment (dissolution vessel or permeation chamber’s donor compartment), maintaining solubilized drug in the acceptor compartment during ex vivo testing remains largely unresolved. This review compiles and critically evaluates the diverse compositions of acceptor media used in ex vivo permeability studies for poorly soluble drugs, highlighting this significant yet underexplored aspect of pharmaceutical science. An algorithm is proposed for selecting solubility-enhancing additives for the acceptor media in ex vivo permeability studies of poorly soluble drugs.
{"title":"Ex vivo permeability study of poorly soluble drugs across gastrointestinal membranes: acceptor compartment media composition","authors":"Andrejs Sitovs , Valentyn Mohylyuk","doi":"10.1016/j.drudis.2024.104214","DOIUrl":"10.1016/j.drudis.2024.104214","url":null,"abstract":"<div><div><em>Ex vivo</em> drug permeability testing across gastrointestinal (GI) membranes is crucial in drug discovery and oral drug delivery. It is a reliable method for drugs with good solubility, but it poses challenges for poorly soluble drugs, which are common in development pipelines today. Although enabling formulations increase the apparent solubility in the GI compartment (dissolution vessel or permeation chamber’s donor compartment), maintaining solubilized drug in the acceptor compartment during <em>ex vivo</em> testing remains largely unresolved. This review compiles and critically evaluates the diverse compositions of acceptor media used in <em>ex vivo</em> permeability studies for poorly soluble drugs, highlighting this significant yet underexplored aspect of pharmaceutical science. An algorithm is proposed for selecting solubility-enhancing additives for the acceptor media in <em>ex vivo</em> permeability studies of poorly soluble drugs.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104214"},"PeriodicalIF":6.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454525","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}
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