Drug Discovery Today: Technologies最新文献_第8页

Identification and characterization of cancer vulnerabilities via targeted protein degradation 通过靶向蛋白降解识别和表征癌症脆弱性

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2018.12.003

Cristina Mayor-Ruiz, Georg E. Winter

引用次数: 24

Ligand-induced genetic degradation as a tool for target validation 配体诱导的遗传降解作为靶标验证的工具

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2018.11.001

Aisha Yesbolatova , Yusuke Tominari , Masato T. Kanemaki

引用次数: 23

Targeted protein degradation mechanisms 靶向蛋白降解机制

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.01.001

Yi Zhang, Christine Loh, Jesse Chen, Nello Mainolfi

引用次数: 30

Monitoring and deciphering protein degradation pathways inside cells 监测和破译细胞内的蛋白质降解途径

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2018.12.001

Danette L. Daniels, Kristin M. Riching, Marjeta Urh

{"title":"Monitoring and deciphering protein degradation pathways inside cells","authors":"Danette L. Daniels, Kristin M. Riching, Marjeta Urh","doi":"10.1016/j.ddtec.2018.12.001","DOIUrl":"10.1016/j.ddtec.2018.12.001","url":null,"abstract":"<div>A new series of therapeutic modalities resulting in degradation of target proteins, termed proteolysis targeting chimeras (PROTACs), hold significant therapeutic potential with possible prolonged pharmacodynamics, improved potency, and ability to target proteins previously thought of as “undruggable”. PROTACs are heterobifunctional small molecules consisting of a target binding handle bridged via a chemical linker to an E3 ligase handle which recruit the E3 ligase and ubiquitin machinery to target proteins, resulting in subsequent ubiquitination and degradation of the target. With the generation of small molecule PROTAC compound libraries for drug discovery, it becomes essential to have sensitive screening technologies to rapidly profile activity and have assays which can clearly inform on performance at the various cellular steps required for PROTAC-mediated degradation. For PROTAC compounds, this has been particularly challenging using either biochemical or cellular assay approaches. Biochemical assays are highly informative for the first part of the degradation process, including optimization of compound binding to targets and interrogation of target:PROTAC:E3 ligase ternary complex formation, but struggle with the remaining steps; recruitment of ternary complex into larger active E3 ligase complexes, ubiquitination, and proteasomal degradation. On the other hand, cellular assays are excellent at determining if the PROTAC successfully degrades the target in its relevant setting but struggle as early development PROTAC compounds are often poorly cell-permeable given their high molecular weight. Additionally, if degradation is not observed in a cellular assay, it is difficult to deconvolute the reason why or at which step there was failure. In this review we will highlight the current approaches along with recent advances to overcome the challenges faced for cellular PROTAC screening, which will enable and advance drug discovery of therapeutic degradation compounds.</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.2018.12.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37332835","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: 41

Targeted protein degradation in vivo with Proteolysis Targeting Chimeras: Current status and future considerations 蛋白质水解靶向嵌合体在体内的靶向蛋白质降解:现状和未来的考虑

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.02.005

Gillian F. Watt , Paul Scott-Stevens , Lu Gaohua

引用次数: 55

PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future 靶向嵌合体(PROTACs)的蛋白水解-过去，现在和未来

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.01.002

Mariell Pettersson, Craig M. Crews

引用次数: 376

Cereblon modulators: Low molecular weight inducers of protein degradation 小脑调节剂:蛋白质降解的低分子量诱导剂

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.02.004

Philip P. Chamberlain, Brian E. Cathers

{"title":"Cereblon modulators: Low molecular weight inducers of protein degradation","authors":"Philip P. Chamberlain, Brian E. Cathers","doi":"10.1016/j.ddtec.2019.02.004","DOIUrl":"10.1016/j.ddtec.2019.02.004","url":null,"abstract":"<div>Targeted protein degradation has become an exciting new paradigm in drug discovery with the potential to target new protein families for therapeutic intervention. In 2010, Hiroshi Handa and colleagues discovered that the drug thalidomide binds to the protein cereblon, a component of the CRL4CRBN E3 ubiquitin ligase. In contrast to the heterobifunctional small molecule degraders reported in the literature, thalidomide is of very low molecular weight (∼258Da) with molecular properties (solubility, metabolic stability, permeability etc) that readily support pharmaceutical dosing. It was subsequently shown that thalidomide and the analogues lenalidomide and pomalidomide are able to degrade the transcription factors Ikaros and Aiolos. CK1α and GSPT1 were subsequently identified as substrates for specific ligands, indicating that this molecular class could be tuned for selective protein degradation. Structural studies showed that the thalidomide analogues bind to a shallow hydrophobic pocket on the surface of cereblon, and scaffold a protein-protein interaction with target proteins. Target proteins do not need any affinity for the cereblon modulators, and as such undruggable, or even unligandable, proteins can be targeted for degradation. A similar mechanism of action was subsequently identified for the clinical molecule indisulam, indicating that low molecular weight degraders are not unique to cereblon. The groundbreaking work on cereblon represents a case study for the discovery and characterization of low molecular weight protein degraders for other ligases.</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.2019.02.004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37332829","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: 58

SNIPERs—Hijacking IAP activity to induce protein degradation snipers -劫持IAP活性诱导蛋白质降解

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2018.12.002

Mikihiko Naito, Nobumichi Ohoka, Norihito Shibata

引用次数: 93

Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins — A review Bromodomain和Extra Terminal (BET)蛋白的小分子PROTAC降解物研究进展

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.04.001

Chao-Yie Yang, Chong Qin, Longchuan Bai, Shaomeng Wang

引用次数: 76

Advanced proteomics approaches to unravel protein homeostasis 先进的蛋白质组学方法揭示蛋白质稳态

Drug Discovery Today: Technologies Pub Date : 2019-04-01 DOI: 10.1016/j.ddtec.2019.02.001

Paola Grandi, Marcus Bantscheff

引用次数: 13