Progress in medicinal chemistry最新文献

{"title":"PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs.","authors":"M Maneiro,&nbsp;E De Vita,&nbsp;D Conole,&nbsp;C S Kounde,&nbsp;Q Zhang,&nbsp;E W Tate","doi":"10.1016/bs.pmch.2021.01.002","DOIUrl":"https://doi.org/10.1016/bs.pmch.2021.01.002","url":null,"abstract":"<p><p>The vast majority of currently marketed drugs rely on small molecules with an 'occupancy-driven' mechanism of action (MOA). Therefore, the efficacy of these therapeutics depends on a high degree of target engagement, which often requires high dosages and enhanced drug exposure at the target site, thus increasing the risk of off-target toxicities (Churcher, 2018 [1]). Although small molecule drugs have been successfully used as treatments for decades, tackling a variety of disease-relevant targets with a defined binding site, many relevant therapeutic targets remain challenging to drug due, for example, to lack of well-defined binding pockets or large protein-protein interaction (PPI) interfaces which resist interference (Dang et al., 2017 [2]). In the quest for alternative therapeutic approaches to address different pathologies and achieve enhanced efficacy with reduced side effects, ligand-induced targeted protein degradation (TPD) has gained the attention of many research groups both in academia and in industry in the last two decades. This therapeutic modality represents a novel paradigm compared to conventional small-molecule inhibitors. To pursue this strategy, heterobifunctional small molecule degraders, termed PROteolysis TArgeting Chimeras (PROTACs) have been devised to artificially redirect a protein of interest (POI) to the cellular protein homeostasis machinery for proteasomal degradation (Chamberlain et al., 2019 [3]). In this chapter, the development of PROTACs will first be discussed providing a historical perspective in parallel to the experimental progress made to understand this novel therapeutic modality. Furthermore, common strategies for PROTAC design, including assays and troubleshooting tips will be provided for the reader, before presenting a compendium of all PROTAC targets reported in the literature to date. Due to the recent advancement of these molecules into clinical trials, consideration of pharmacokinetics and pharmacodynamic properties will be introduced, together with the biotech landscape that has developed from the success of PROTACs. Finally, an overview of subsequent strategies for targeted protein degradation will be presented, concluding with further scientific quests triggered by the invention of PROTACs.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"60 ","pages":"67-190"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2021.01.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39249141","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}

{"title":"An overview of DNA-encoded libraries: A versatile tool for drug discovery.","authors":"Daniel Madsen,&nbsp;Carlos Azevedo,&nbsp;Iolanda Micco,&nbsp;Lars Kolster Petersen,&nbsp;Nils Jakob Vest Hansen","doi":"10.1016/bs.pmch.2020.03.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2020.03.001","url":null,"abstract":"<p><p>DNA-encoded libraries (DELs) are collections of small molecules covalently attached to amplifiable DNA tags carrying unique information about the structure of each library member. A combinatorial approach is used to construct the libraries with iterative DNA encoding steps, facilitating tracking of the synthetic history of the attached compounds by DNA sequencing. Various screening protocols have been developed which allow protein target binders to be selected out of pools containing up to billions of different small molecules. The versatile methodology has allowed identification of numerous biologically active compounds and is now increasingly being adopted as a tool for lead discovery campaigns and identification of chemical probes. A great focus in recent years has been on developing DNA compatible chemistries that expand the structural diversity of the small molecule library members in DELs. This chapter provides an overview of the challenges and accomplishments in DEL technology, reviewing the technological aspects of producing and screening DELs with a perspective on opportunities, limitations, and future directions.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"59 ","pages":"181-249"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2020.03.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37895681","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}

{"title":"P2X7 receptor antagonists for the treatment of systemic inflammatory disorders.","authors":"Christine F Gelin,&nbsp;Anindya Bhattacharya,&nbsp;Michael A Letavic","doi":"10.1016/bs.pmch.2019.11.002","DOIUrl":"https://doi.org/10.1016/bs.pmch.2019.11.002","url":null,"abstract":"<p><p>P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been investigated and disclosed in patent applications or primary literature since 2015. While a crystal structure of the receptor to aid in the design of novel chemical structures remains elusive, many of the chemotypes that have been disclosed contain similarities, with an amide motif present in all series that have been explored to date. Several of the recent antagonists described are brain penetrant, and two compounds are currently in clinical trials for CNS indications. Additionally, brain penetrant PET ligands have been developed that aid in measuring target engagement and these ligands can potentially be used as biomarkers.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"59 ","pages":"63-99"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2019.11.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37896010","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}

{"title":"Preface.","authors":"David R Witty,&nbsp;Brian Cox","doi":"10.1016/S0079-6468(20)30010-2","DOIUrl":"https://doi.org/10.1016/S0079-6468(20)30010-2","url":null,"abstract":"","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"59 ","pages":"ix-x"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0079-6468(20)30010-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37896015","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}

{"title":"Contributors","authors":"","doi":"10.1016/s0079-6468(20)30009-6","DOIUrl":"https://doi.org/10.1016/s0079-6468(20)30009-6","url":null,"abstract":"","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/s0079-6468(20)30009-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"55877970","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}

{"title":"Small molecules-Giant leaps for immuno-oncology.","authors":"Lisa Kötzner,&nbsp;Bayard Huck,&nbsp;Sakshi Garg,&nbsp;Klaus Urbahns","doi":"10.1016/bs.pmch.2019.11.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2019.11.001","url":null,"abstract":"<p><p>Immuno-oncology therapies are revolutionizing the oncology landscape with checkpoint blockade becoming the treatment backbone for many indications. While inspiring, much work remains to increase the number of cancer patients that can benefit from these treatments. Thus, a new era of immuno-oncology research has begun which is focused on identifying novel combination regimes that lead to improved response rates. This review highlights the significance of small molecules in this approach and illustrates the huge progress that has been made to date.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"59 ","pages":"1-62"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2019.11.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37895677","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}

{"title":"Discovery and development of ASK1 inhibitors.","authors":"Reginald Brys,&nbsp;Karl Gibson,&nbsp;Tanja Poljak,&nbsp;Steven Van Der Plas,&nbsp;David Amantini","doi":"10.1016/bs.pmch.2020.02.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2020.02.001","url":null,"abstract":"<p><p>Aberrant activation of mitogen-activated protein kinases (MAPKs) like c-Jun N-terminal kinase (JNK) and p38 is an event involved in the pathophysiology of numerous human diseases. The apoptosis signal-regulating kinase 1 (ASK1) is an upstream target that gets activated only under pathological conditions and as such is a promising target for therapeutic intervention. In the first part of this review the molecular mechanisms leading to ASK1 activation and regulation will be described as well as the evidences supporting a pathogenic role for ASK1 in human disease. In the second part, an update on drug discovery efforts towards the discovery and development of ASK1-targeting therapies will be provided.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"59 ","pages":"101-179"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2020.02.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37895679","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}

{"title":"Copyright","authors":"","doi":"10.1016/s0079-6468(20)30007-2","DOIUrl":"https://doi.org/10.1016/s0079-6468(20)30007-2","url":null,"abstract":"","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/s0079-6468(20)30007-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"55877952","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}

{"title":"Covalent binders in drug discovery.","authors":"Anil Vasudevan,&nbsp;Maria A Argiriadi,&nbsp;Aleksandra Baranczak,&nbsp;Michael M Friedman,&nbsp;Julia Gavrilyuk,&nbsp;Adrian D Hobson,&nbsp;Jonathan J Hulce,&nbsp;Sami Osman,&nbsp;Noel S Wilson","doi":"10.1016/bs.pmch.2018.12.002","DOIUrl":"https://doi.org/10.1016/bs.pmch.2018.12.002","url":null,"abstract":"<p><p>Covalent modulation of protein function can have multiple utilities including therapeutics, and probes to interrogate biology. While this field is still viewed with scepticism due to the potential for (idiosyncratic) toxicities, significant strides have been made in terms of understanding how to tune electrophilicity to selectively target specific residues. Progress has also been made in harnessing the potential of covalent binders to uncover novel biology and to provide an enhanced utility as payloads for Antibody Drug Conjugates. This perspective covers the tenets and applications of covalent binders.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"58 ","pages":"1-62"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2018.12.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37238417","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}

{"title":"Rewriting the (tran)script: Application to spinal muscular atrophy.","authors":"Hasane Ratni,&nbsp;Lutz Mueller,&nbsp;Martin Ebeling","doi":"10.1016/bs.pmch.2018.12.003","DOIUrl":"https://doi.org/10.1016/bs.pmch.2018.12.003","url":null,"abstract":"<p><p>Targeting RNA drastically expands our target space to therapeutically modulate numerous cellular processes implicated in human diseases. Of particular interest, drugging pre-mRNA splicing appears a very viable strategy; to control levels of splicing product by promoting the inclusion or exclusion of exons. After describing the concept of \"splicing modulation\", this chapter will cover the outstanding progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of spinal muscular atrophy using two therapeutic modalities: splice switching oligonucleotides and small molecules. This review discusses the vital but feasible requirement for such drugs to deliver selectivity, and critical safety aspects are highlighted. Transformational medicines such as those developed to treat SMA are likely just the beginning of this story.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"58 ","pages":"119-156"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2018.12.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37063941","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}