Drug Discovery Today: Technologies最新文献

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A critical evaluation of the approaches to targeted protein degradation for drug discovery 药物发现靶向蛋白质降解方法的关键评估。
Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.02.002
Rajesh Chopra, Amine Sadok, Ian Collins
{"title":"A critical evaluation of the approaches to targeted protein degradation for drug discovery","authors":"Rajesh Chopra,&nbsp;Amine Sadok,&nbsp;Ian Collins","doi":"10.1016/j.ddtec.2019.02.002","DOIUrl":"10.1016/j.ddtec.2019.02.002","url":null,"abstract":"<div><p>There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional molecules that bind the target for ubiquitin mediated degradation by complexing them with Cereblon (CRBN), von Hippel-Lindau or other E-3 ligases. Alternatively, E-3 ligase receptors such as CRBN or DCAF15 can also be used as a ‘template’ to bind IMiD or sulphonamide like compounds to degrade multiple context specific proteins by the selected E-3 ligases. The ‘template approach’ results in the degradation of neo-substrates, some of which would be difficult to drug using conventional approaches. The chemical properties necessary for drug discovery, the rules by which neo-substrates are selected by E-3 ligase receptors and defining the optimal components of the ubiquitin proteasome for protein degradation are still to be fully elucidate. Theis review will aim to critically evaluate the different approaches and principles emerging for targted protein degradation.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2019.02.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37332833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 30
Miniaturised ‘antibody’-drug conjugates for solid tumours? 用于实体瘤的小型化“抗体”-药物结合物?
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.09.006
Mahendra P. Deonarain
{"title":"Miniaturised ‘antibody’-drug conjugates for solid tumours?","authors":"Mahendra P. Deonarain","doi":"10.1016/j.ddtec.2018.09.006","DOIUrl":"10.1016/j.ddtec.2018.09.006","url":null,"abstract":"<div><p><span><span>With Antibody-Drug Conjugate strategies firmly focussed on the precise conjugation to the large protein Immunoglobulin-G format, it is easy to miss the more recent technological innovations in small-format drug conjugates<span>. Here, the targeting ligand can be at 50–95% reduced in size, or even smaller if peptidic in nature. Antibody domains or alternative binding scaffolds, chemically-modified with ultra-potent cytotoxic payloads offer an alternative approach for oncology therapeutics, promising a wider therapeutic window by virtue of superior </span></span>solid tumour penetration properties and more rapid system clearance. Many of the traditional </span>ADC concepts still apply, but as these miniaturised ADCs enter the clinic over the next 2–3 years, we will learn whether these new features translate to patient benefits.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.09.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 15
Bispecifics and antibody–drug conjugates: A positive synergy 双特异性和抗体-药物缀合物:积极的协同作用
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.09.003
Antoine Maruani
{"title":"Bispecifics and antibody–drug conjugates: A positive synergy","authors":"Antoine Maruani","doi":"10.1016/j.ddtec.2018.09.003","DOIUrl":"10.1016/j.ddtec.2018.09.003","url":null,"abstract":"<div><p><span><span>Bispecific antibodies<span> (BsAbs) are antibodies with two different paratopes<span>. In the past decade, advances in protein engineering have enabled the development of more than 100 formats of BsAbs. With two BsAbs approved for therapeutic use and more than 60 in </span></span></span>clinical trials, this research area has shifted from being effervescent to being a mainstream therapeutic development topic. In parallel, recent progress in protein conjugation and cytotoxicity of </span>small molecule drugs has resulted in a boom in monospecific antibody therapeutics development such as antibody–drug conjugates (ADCs). Recent examples have demonstrated how BsAbs approaches can be used to generate ADCs with better efficacy and safety profile. Rather than examining these two different yet similar areas independently, this minireview will explore the potential synergies that can exist between them.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.09.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 28
Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy 抗体偶联纳米颗粒作为抗体药物偶联化疗的一种新形式
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.10.003
Michael C. Johnston, Christopher J. Scott
{"title":"Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy","authors":"Michael C. Johnston,&nbsp;Christopher J. Scott","doi":"10.1016/j.ddtec.2018.10.003","DOIUrl":"10.1016/j.ddtec.2018.10.003","url":null,"abstract":"<div><p><span><span><span>Antibody conjugated </span>nanoparticles (ACNPs) represent a novel strategy for the development of therapies exploiting antibodies to augment the delivery of chemotherapy payloads. Following in the footsteps of the success of </span>antibody drug conjugates<span> (ADCs), ACNPs are only now reaching clinical evaluation. In this review we discuss the success of ADCs and explore the opportunities ACNPs offer, such as broad chemotherapy payload selection, high drug to antibody ratios and the ability to finely tailor drug release in comparison to ADCs. The ability of ACNPs to elicit increased </span></span>avidity due to multivalent effects and the potential to use these modular platforms in immunotherapeutic approaches is also explored. Through addressing challenges that still remain in bringing these complex formulations to the clinic, ACNPs hold obvious potential for the treatment of a wide range of cancers and other diseases where selective targeting of drug agents is essential.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.10.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 57
Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: Is mechanism related to systemic toxicity? 使用吡咯苯二氮卓类药物和相关的共价结合dna相互作用分子作为ADC有效载荷:机制是否与全身毒性有关?
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.10.004
Paul J.M. Jackson , Syafiq Kay , Ilona Pysz , David E. Thurston
{"title":"Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: Is mechanism related to systemic toxicity?","authors":"Paul J.M. Jackson ,&nbsp;Syafiq Kay ,&nbsp;Ilona Pysz ,&nbsp;David E. Thurston","doi":"10.1016/j.ddtec.2018.10.004","DOIUrl":"10.1016/j.ddtec.2018.10.004","url":null,"abstract":"<div><p>Antibody-drug conjugates<span> (ADCs) consist of monoclonal antibodies<span><span> (mAbs) or antibody fragments conjugated to biologically active molecules (usually highly cytotoxic small molecules) through chemical linkers. Although no ADCs containing covalent-binding DNA-interactive payloads have yet been approved (although two containing the DNA-cleaving payload calicheamicin have), of those in </span>clinical trials systemic toxicities are beginning to emerge. This article discusses the observed toxicities in relation to the structures and mechanisms of action of payload type.</span></span></p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.10.004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 16
Site-specific chelator-antibody conjugation for PET and SPECT imaging with radiometals 位点特异性螯合剂-抗体偶联PET和SPECT成像与放射性金属
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.10.002
Mauricio Morais, Michelle T. Ma
{"title":"Site-specific chelator-antibody conjugation for PET and SPECT imaging with radiometals","authors":"Mauricio Morais,&nbsp;Michelle T. Ma","doi":"10.1016/j.ddtec.2018.10.002","DOIUrl":"10.1016/j.ddtec.2018.10.002","url":null,"abstract":"<div><p>Antibodies and their derivatives radiolabelled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo. Chelators that are covalently attached to antibodies allow radiolabelling with metallic PET and SPECT radioisotopes. Conventional strategies for chelator-protein conjugation generate heterogeneous mixtures of bioconjugates that can exhibit reduced affinity for their receptor targets, and undesirable biodistribution and pharmacokinetics. Recent advances in bioconjugation technology enable site-specific modification to generate well-defined constructs with superior properties. Herein we survey existing site-specific chelator-protein conjugation methods. These include chelator attachment to cysteines/disulfide bonds or the glycan region of the antibody, enzyme-mediated chelator conjugation, and incorporation of sequences of amino acids that chelate the radiometal. Such technology will allow better use of PET and SPECT imaging in the development of antibody-based therapies.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.10.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 45
Antibody – Drug conjugates (ADC) – Drug discovery today: Technologies 抗体-药物偶联物(ADC) -今天的药物发现:技术
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.11.003
Vijay Chudasama
{"title":"Antibody – Drug conjugates (ADC) – Drug discovery today: Technologies","authors":"Vijay Chudasama","doi":"10.1016/j.ddtec.2018.11.003","DOIUrl":"10.1016/j.ddtec.2018.11.003","url":null,"abstract":"","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.11.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 6
Drawing lessons from the clinical development of antibody-drug conjugates 从抗体-药物偶联物的临床发展中吸取教训
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.10.001
Robert Lyon
{"title":"Drawing lessons from the clinical development of antibody-drug conjugates","authors":"Robert Lyon","doi":"10.1016/j.ddtec.2018.10.001","DOIUrl":"10.1016/j.ddtec.2018.10.001","url":null,"abstract":"<div><p>The antibody-drug conjugate (ADC) field has seen a remarkable expansion in the number of entrants in clinical studies. Many of these agents employ newer conjugation technologies that have been developed over the last decade that confer various attributes to the ADCs prepared with them, including stability, potency, and homogeneity. In many cases, these new ADCs appear demonstrably superior to earlier technologies in preclinical models of activity and toxicology, but the degree to which these improvements will translate to the clinic is only starting to be seen. Many of these technologies are now competing head-to-head by targeting the same antigen in similar patient populations, allowing for a direct comparison of their clinical performance properties. As lessons from these experiences feed back into discovery research, future iterations of ADC design may be expected to bring improved therapeutics into the clinic.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.10.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36786614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 40
Minireview: Addressing the retro-Michael instability of maleimide bioconjugates 综述:探讨马来酰亚胺生物偶联物的反迈克尔不稳定性
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.07.002
Peter A. Szijj, Calise Bahou, Vijay Chudasama
{"title":"Minireview: Addressing the retro-Michael instability of maleimide bioconjugates","authors":"Peter A. Szijj,&nbsp;Calise Bahou,&nbsp;Vijay Chudasama","doi":"10.1016/j.ddtec.2018.07.002","DOIUrl":"10.1016/j.ddtec.2018.07.002","url":null,"abstract":"<div><p><span>Bioconjugation<span><span>, the modification of biological macromolecules such as proteins, is an up and coming area in the field of chemical biology. Antibody-drug </span>conjugates<span> (ADCs), combining the antigen-selectivity of natural antibodies with the cytotoxic potency of small molecule drugs, are a powerful therapeutic technology. Four such constructs are currently on the market for cancer therapy. However, the conjugation methodology employed in these therapeutics is far from ideal. Herein we provide an overview on methods that attempt to increase the safety and efficacy of ADCs </span></span></span><em>via</em> “self-hydrolysing maleimides” or by improving the stability of maleimide-conjugates by other means. We find that some very promising reagents have been reported, however the mechanism by which each of these reagents acts is not clear, thus limiting rational design for some strategies.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.07.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 61
Exploring alternative antibody scaffolds: Antibody fragments and antibody mimics for targeted drug delivery 探索替代抗体支架:靶向药物递送的抗体片段和抗体模拟物
Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI: 10.1016/j.ddtec.2018.10.005
Daniel A. Richards
{"title":"Exploring alternative antibody scaffolds: Antibody fragments and antibody mimics for targeted drug delivery","authors":"Daniel A. Richards","doi":"10.1016/j.ddtec.2018.10.005","DOIUrl":"10.1016/j.ddtec.2018.10.005","url":null,"abstract":"<div><p>The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. in antibody–drug conjugates (ADCs). The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community; many major companies have dedicated ADC research programmes. However, despite the advantages, the field of ADCs has failed to live up to its full potential. Studies have emerged suggesting that traditional IgG scaffolds may not be the optimal format for targeted payload delivery. In response, the protein engineering community has begun to explore alternative high-binding protein scaffolds as antibody mimics. In this short review I will summarise the generation, modification, and application of emerging antibody fragments and synthetic antibody mimics, with a focus on their use as drug carriers. The review aims to highlight the advantages of antibody mimics, and how they could be employed to overcome the issues and limitations of traditional ADCs.</p></div>","PeriodicalId":36012,"journal":{"name":"Drug Discovery Today: Technologies","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ddtec.2018.10.005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36774443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 50
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