Stefan Knapp
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View article: Enantioselective protein affinity selection mass spectrometry (E-ASMS)
Enantioselective protein affinity selection mass spectrometry (E-ASMS) Open
We report an enantioselective protein affinity selection mass spectrometry screening approach (E-ASMS) that enables the detection of weak binders, informs on selectivity, and generates orthogonal confirmation of binding. After method devel…
View article: Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2
Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2 Open
Developing new E3 ligase ligands for the design of heterobivalent molecules, such as PROteolysis TArgeting Chimeras (PROTACs), requires careful evaluation of target engagement (TE). Characterizing protein-protein interactions (PPIs) is the…
View article: Targeting bacterial kinases as a strategy to counteract antibiotic resistance
Targeting bacterial kinases as a strategy to counteract antibiotic resistance Open
Antibiotic resistance is rapidly emerging as one of the most critical health threats, with resistant microorganisms progressively diminishing the effectiveness of established antibiotics. As a result, the development of therapeutic approac…
View article: Inhibitors supercharge kinase turnover through native proteolytic circuits
Inhibitors supercharge kinase turnover through native proteolytic circuits Open
Targeted protein degradation is a pharmacological strategy that relies on small molecules such as proteolysis-targeting chimeras (PROTACs) or molecular glues, which induce proximity between a target protein and an E3 ubiquitin ligase to pr…
View article: Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1
Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1 Open
OGG1 lyase-activators are organocatalytic switches that enhance OGG1 initiated DNA repair by stimulating rudimentary activities through direct catalytic involvement, establishing de novo enzymatic functions on a widened substrate scope.
View article: Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)
Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK) Open
STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression and lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with imp…
View article: Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer
Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer Open
Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including non-small cell lung cancer (NSCLC). We previously reported SBP-7455 , a dual inhibitor of unc-51-like kinase 1 (ULK1) and its …
View article: Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2
Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2 Open
Developing new E3 ligase ligands for the design of heterobivalent molecules, such as PROteolysis TArgeting Chimeras (PROTACs), requires careful evaluation of target engagement (TE). Characterizing protein-protein interactions (PPIs) is the…
View article: Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1
Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1 Open
Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, …
View article: Click. Screen. Degrade. A Miniaturized D2B Workflow for rapid PROTAC Discovery
Click. Screen. Degrade. A Miniaturized D2B Workflow for rapid PROTAC Discovery Open
SUMMARY Targeted protein degradation is one of the fastest developing fields in medicinal chemistry and chemical biology. Despite significant development in assay technologies and inhibitor discovery, the development of PROTACs remains a c…
View article: Structural analysis of TRIM family PRYSPRY domains and its implications for E3-ligand design
Structural analysis of TRIM family PRYSPRY domains and its implications for E3-ligand design Open
Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of RING-type E3 ubiquitin ligases and are attractive targets for the development of novel degraders that exploit the ubiquitin-proteasome pathway. More than half of…
View article: Un-LOK-ing a new approach for conformational selective targeting of STK10 (LOK)
Un-LOK-ing a new approach for conformational selective targeting of STK10 (LOK) Open
STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression or lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with impa…
View article: Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion
Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion Open
Proteolysis-targeting chimeras (PROTACs) co-op the ubiquitin system for targeted protein degradation, creating opportunities to interrogate cellular functions of proteins through “chemical knockdown”. However, matched pairs of protein degr…
View article: Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor
Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor Open
Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding…
View article: Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase
Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase Open
The bifunctional soluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases. Although potent inhibitors targeting each domain are available, sEH-PROTACs offer the unique ability to simultaneously block …
View article: Type II kinase inhibitors that target Parkinson’s disease–associated LRRK2
Type II kinase inhibitors that target Parkinson’s disease–associated LRRK2 Open
Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson’s disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowl…
View article: Click Chemistry Enables Rapid Development of Potent sEH PROTACs Using a Direct-to-Biology Approach
Click Chemistry Enables Rapid Development of Potent sEH PROTACs Using a Direct-to-Biology Approach Open
The Direct-to-Biology (D2B) approach enables biological screening of crude reaction mixtures, eliminating the need for purification steps and thereby accelerating drug discovery. In this study, we developed a miniaturized D2B platform for …
View article: Native Taylor/Non‐Taylor Dispersion–Mass Spectrometry (TNT‐MS) Allows Rapid Protein Desalting and Multiplexed, Label‐Free Ligand Screening
Native Taylor/Non‐Taylor Dispersion–Mass Spectrometry (TNT‐MS) Allows Rapid Protein Desalting and Multiplexed, Label‐Free Ligand Screening Open
Native mass spectrometry (MS) is an important technique in structural biology and drug discovery, due to its ability to study non‐covalent assemblies in the gas phase. Drawbacks include the incompatibility of electrospray ionization (ESI) …
View article: Screening assay to monitor mono-ADP-ribosylhydrolase activity of viral macrodomains in cells
Screening assay to monitor mono-ADP-ribosylhydrolase activity of viral macrodomains in cells Open
Mono-ADP-ribosylation, a regulatory modification of both protein and nucleic acids, has been implicated in innate immunity. In cells, this modification is catalyzed by PARP enzymes, some of which are induced in response to interferons. Mon…
View article: Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors
Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors Open
Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding…
View article: Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor
Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor Open
Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket created by an αC-out/DFG-out conformation. This inactive conformation results in a large expansion…
View article: Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity
Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity Open
Chronic inflammatory diseases are a significant global burden and are associated with dysregulated resolution of inflammation. Therefore, promoting the process of resolution is a promising therapeutic approach. This study presents the pote…
View article: LOPAC library screening identifies suramin as a TRIM21 binder with a unique binding mode revealed by crystal structure
LOPAC library screening identifies suramin as a TRIM21 binder with a unique binding mode revealed by crystal structure Open
Differential scanning fluorimetry screening of the Library of Pharmacologically Active Compounds (LOPAC) identified four hits for the PRYSPRY domain of the human E3 ligase tripartite motif-containing protein 21 (TRIM21). Isothermal titrati…
View article: Workflow for E3 Ligase Ligand Validation for PROTAC Development
Workflow for E3 Ligase Ligand Validation for PROTAC Development Open
Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligan…
View article: Correction: LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains
Correction: LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains Open
[This corrects the article DOI: 10.1371/journal.pbio.3001427.].