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Articles by Georg E. Winter
Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation
Abstract Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4DCAF16 and CRL1FBXO22 in parallel to degrade SMARCA2/4.
Disruption of the SAGA CORE triggers collateral degradation of KAT2A
Abstract The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex regulates gene expression through histone acetylation at promoters, mediated by its histone acetyl transferase (HAT), KAT2A. While SAGA structure and function are well characterised, mechanisms controlling the stability of individual subunits, including KAT2A, remain unclear.
High-throughput ligand diversification to discover chemical inducers of proximity - Nature Chemical Biology
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Abstract Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein–ligand interface.
By James B. Shaum, Erica A. Steen, Daniela V. Wenge, Hakyung Cheong, Moritz Hunkeler, Eric M. Bilotta, Lauren Hargis, Timothy R. Bishop, Trever R. Carter, Matthias Hinterndorfer, Lucas Dada, Wen-Ji He, Fabian Offensperger, Hirotake Furihata, Charlie Hatton, Yanhe Wen, Benjamin Cravatt, Keary M. Engle, Katherine A. Donovan, Bruno Melillo, Seiya Kitamura, Alessio Ciulli, Scott Armstrong, Eric S. Fischer, Georg E. Winter, Michael Erb, Jordan Janowski, Zoe J. Rutter, Paige A. Barta, Abby M. Thornhill, Natalia Milosevich, Sydney R. Schweber
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Nature
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Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3 - Nature Chemistry
Abstract Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein–protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (−)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism.
Höchstädt: Adventliche Stunde im Schloss Höchstädt
In den vergangenen Jahren entwickelte sich das Adventskonzert im Rittersaal des Höchstädter Schlosses zu einer beliebten Tradition. Als Auftakt erklangen die Männerstimmen des Projektchores „Go°d Will“ unter der Leitung von Ulrich Weber zunächst aus dem „Off“. Danach wechselten sie sich, begleitet von zarten Frauenstimmen und Kontrabass, mit der Solistin Isabel Bahmann ab und erfüllten den Raum mit dem sphärischen „Canticle“ des irischen Komponisten Liam Lawton.
Höchstädt: Adventliche Stunden im Schloss
Das traditionelle Adventskonzert im Schloss Höchstädt findet am Samstag, den 20. Dezember, statt. Beginn der beiden Konzerte ist jeweils um 17 Uhr und 19 Uhr. Georg Winter, der seit 1994 diese adventliche Stunde organisiert, lädt dazu die gesamte Bevölkerung herzlich ein. Gäste können sich auf einen musikalischen Genuss im stimmungsvollen Ambiente des Höchstädter Schlosses freuen.
Opportunities in proximity modulation: Bridging academia and industry
Keywords targeted protein degradation TPD molecular glue degraders MGDs PROTACs E3 ligases proximity induction academic-industrial collaboration public-private partnerships innovation hubs technology transfer Introduction Proximity induction is a powerful mechanism utilizing small molecules to reprogram cellular machineries and trigger novel biological functions. The pharmaceutically best understood outcome of proximity induction is targeted protein degradation (TPD).
Targeted protein degradation for cancer therapy - Nature Reviews Cancer
Abstract Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins.
Neue Kryptowährungen: Wie kommen sie eigentlich auf den Markt?
Kryptowährungen sind ein fester Bestandteil der Finanzwelt. Was einst nur etwas für die absoluten Techniknerds galt, hat sich zu einem riesigen Phänomen entwickelt. Banken, Investoren und auch Regulierungsbehörden werden von dem ehemaligen Nischenprodukt weiter auf Trab gehalten, um zeitnah Produkte und Regelungen anzubieten. Neben etablierten Kryptowährungen wie dem Bitcoin gibt es eine ständig wachsende Zahl an neueren Kryptowährungen, welche regelmäßig auf den Markt kommen.
Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs
Introduction Click to copy section linkSection link copied! Small molecules play a pivotal role as chemical probes, facilitating the dose- and time-dependent modulation of protein function to shed light on biological mechanisms. Throughout history, small molecules have also formed the cornerstone of many pharmaceutical treatments for human diseases. Despite the rising interest in biologics or cell-based therapies, most FDA-approved drugs are small-molecules.
Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation - Nature Chemical Biology
Abstract Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins.
Targeted protein degradation via intramolecular bivalent glues - Nature
Abstract Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1,2,3,4.
Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype - Nature Communications
Abstract Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of autophagy we combine arylidene-indolinones reported to bind the autophagy-related LC3B-protein and ligands of the PDEδ lipoprotein chaperone, the BRD2/3/4-bromodomain containing proteins and the BTK- and BLK kinases.
Design principles for cyclin K molecular glue degraders - Nature Chemical Biology
Abstract Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase.
Pharmacological perturbation of the phase-separating protein SMNDC1 - Nature Communications
Abstract SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain.
Toolmakers for the Future : International Network for Environmental Management
Record: found Abstract: found Book: found Is Open Access Publication date (Print): Subjects: , , , , , , Keywords: , , , , There is no author summary for this book yet. Authors can add summaries to their books on ScienceOpen to make them more accessible to a non-specialist audience. Dr Georg Winter developed a systematic model for integrating environmental considerations into all aspects of company operations of his family-owned business starting in the late 1960s.
CIDE-stepping E3s - Nature Chemical Biology
Small-molecule-mediated targeted protein degradation (TPD) relies on the recruitment of a target protein of interest to an E3 ligase. A new study indicates how direct target recruitment to the 26S proteasome can bypass this requirement. Of the 600 known E3 ligases, approximately 1% have been identified as tractable for TPD. CRL4CRBN and CRL2VHL are the most frequently used, and PROTACs leveraging each of these ligases have entered human clinical investigation3.
Identification and selectivity profiling of small-molecule degraders via multi-omics approaches
An J. Ponthier C.M. Sack R. Seebacher J. Stadler M.B. Donovan K.A. Fischer E.S. pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4 CRBN ubiquitin ligase. Nat. Commun. 2017; 8: 1-11 Backus K.M. Correia B.E. Lum K.M. Forli S. Horning B.D. González-Páez G.E. Chatterjee S. Lanning B.R. Teijaro J.R. Olson A.J. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature. 2016; 534: 570-574 Bar-Peled L.
The role of reversible and irreversible covalent chemistry in targeted protein degradation
Abegg D. Gasparini G. Hoch D.G. Shuster A. Bartolami E. Matile S. Adibekian A. Strained cyclic disulfides enable cellular uptake by reacting with the transferrin receptor. J. Am. Chem. Soc. 2017; 139: 231-238 An S. Fu L. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine. 2018; 36: 553-562 Arrowsmith C.H. Audia J.E. Austin C. Baell J. Bennett J. Blagg J. Bountra C. Brennan P.E. Brown P.J. Bunnage M.E. et al.
Fast-acting chemical tools to delineate causality in transcriptional control
Summary Multi-dimensional omics profiling continues to illuminate the complexity of cellular processes. Because of difficult mechanistic interpretation of phenotypes induced by slow perturbation, fast experimental setups are increasingly used to dissect causal interactions directly in cells. Here we review a growing body of studies that leverage rapid pharmacological perturbation to delineate causality in gene control.
Clemens Tönnies: Der Fleischkönig, den das Virus in die Krise stürzte
Plus Clemens Tönnies führt Europas größtes Schlacht-Imperium. Und den Fußballklub Schalke 04. Nun steht der Patriarch am Pranger. Über einen, der keinen Widerspruch duldet. Von Robert Peters, Stefan Schelp, Georg Winter, Claudia Benz und Michael Munkler Irgendwann, wahrscheinlich schon bald, machen sie einen Film daraus. Der Titel könnte dann lauten: „Aufstieg und Fall des Schweinebarons“. Oder „Wie der Schnitzelkönig sein Reich verlor“. Hauptsache reißerisch. Hauptsache Rampenlicht.
Expanding the Degradable Proteome: Designing PROTACs by the Book
In this issue of Cell Chemical Biology, Li et al., 2020 Li Z. Pinch B.J. Olson C.M. Donovan K.A. Nowak R.P. Mills C.E. Scott D.A. Doctor Z.M. Eleuteri N.A. Chung M. et al. Development and Characterization of a Wee1 Kinase Degrader. Cell Chem. Biol. 2020; 27 ( ) : 57-65 , Hsu et al., 2020 Hsu J.H.-R. Rasmusson T. Robinson J. Pachl F. Read J. Kawatkar S. O’ Donovan D.H. Bagal S. Code E. Rawlins P. et al. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem. Biol.
Cell Press: Cell Press
BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment
Publication HistoryPublished: June 29, 2017Accepted: June 2, 2017; Received in revised form: March 14, 2017; Received: December 6, 2016;
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