A5075720582- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Microtubule and mitosis dynamics
- Protein Degradation and Inhibitors
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Quinazolinone synthesis and applications
- Advanced Breast Cancer Therapies
- Click Chemistry and Applications
- Melanoma and MAPK Pathways
- Cholinesterase and Neurodegenerative Diseases
- Wnt/β-catenin signaling in development and cancer
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Chronic Lymphocytic Leukemia Research
- Medical Imaging Techniques and Applications
- Biochemical and Molecular Research
- Cancer Treatment and Pharmacology
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
University of North Carolina at Chapel Hill
2016-2025
GlaxoSmithKline (United States)
2015-2024
University of North Carolina Health Care
2019-2023
Joint Center for Structural Genomics
2021-2023
Structural Genomics Consortium
2020
Communities In Schools of Orange County
2017-2020
Research Triangle Park Foundation
2013-2015
For kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed measure binding or enzymatic inhibition, such approaches can fail accurately predict engagement in cells. Here we report the application an energy transfer technique that enabled first broad-spectrum, equilibrium-based approach quantitatively profile occupancy and compound affinity live Using this method, performed profiling for...
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of majority 500+ human protein remains unknown. We have developed physical virtual collections small molecule inhibitors, which we call chemogenomic sets, that designed to inhibit catalytic almost half kinases. In this manuscript share our progress towards generation a comprehensive kinase set (KCGS), release kinome profiling data large inhibitor (Published Kinase...
Abstract Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi’s) as small molecule drugs and chemical probes intracellular CDK function. However, conflicting data has been reported on inhibitory potency CDKi’s a systematic characterization affinity selectivity against CDKs is lacking. We developed panel cell-permeable energy transfer quantify target occupancy for all 21 human in live cells, present comprehensive evaluation isozyme...
We describe the assembly and annotation of a chemogenomic set protein kinase inhibitors as an open science resource for studying biology. The only includes that show potent inhibition narrow spectrum activity when screened across large panel biochemical assays. Currently, contains 187 cover 215 human kinases. (KCGS), current Version 1.0, is most highly annotated selective available to researchers use in cell-based screens.
β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates signaling internalization degradation the complex. Here, using gain-of-function screen kinome, we report that AP2 associated kinase 1 (AAK1), known enhancer, inhibits signaling. Reciprocally, AAK1...
Abstract Despite decades of intensive search for compounds that modulate the activity particular protein targets, a large proportion human kinome remains as yet undrugged. Effective approaches are therefore required to map massive space unexplored compound–kinase interactions novel and potent activities. Here, we carry out crowdsourced benchmarking predictive algorithms kinase inhibitor potencies across multiple families tested on unpublished bioactivity data. We find top-performing...
Deep generative neural networks have been used increasingly in computational chemistry for de novo design of molecules with desired properties. Many deep learning approaches employ reinforcement optimizing the target properties generated molecules. However, success this approach is often hampered by problem sparse rewards as majority are expectedly predicted inactives. We propose several technical innovations to address and improve balance between exploration exploitation modes learning. In...
Covalent EGFR family inhibitors bind to and induce the degradation of pseudokinase TRIB2 kill cancer cells.
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes several these have been made available to academia. However, probe-associated data control compounds, such as inactive structurally related molecules their associated data, generally not accessible. lack guidance makes it difficult for researchers decide which tools choose....
We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as collateral target. identified 18 potent lacking GAK activity. Together, this chemical probe set can be used to interrogate biology.
Abstract 4‐Anilinoquinolines were identified as potent and narrow‐spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator viral bacterial entry into host cells. Optimization 4‐anilino group 6,7‐quinoline substituents produced GAK with nanomolar activity, over 50 000‐fold selectivity relative to other members numb‐associated (NAK) subfamily, a compound (6,7‐dimethoxy‐ N ‐(3,4,5‐trimethoxyphenyl)quinolin‐4‐amine; 49 ) kinome profile. These compounds may be useful...
Article19 August 2019Open Access Transparent process E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin loss and Chk1 inhibition Kamila Burdova Department of Oncology, Medical Research Council Institute for Radiation University Oxford, UK Search more papers by this author Hongbin Yang Roberta Faedda Samuel Hume Jagat Chauhan Nuffield Clinical Medicine, Ludwig Cancer Research, Headington, Daniel Ebner Target Discovery Institute, Benedikt M Kessler Iolanda Vendrell...
Inhibition of the protein kinase CSNK2 with any 30 specific and selective inhibitors representing different chemotypes, blocked replication pathogenic human, bat, murine β-coronaviruses. The potency in-cell CSNK2A target engagement across set correlated antiviral activity genetic knockdown confirmed essential role holoenzyme in β-coronavirus replication. Spike endocytosis was by inhibition, indicating that due part to a suppression viral entry. inhibition may be viable for development...
Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound selectively inhibits CK2α CK2α' when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks key hinge-binding nitrogen (7) was designed on the basis structural studies. 7 does not bind or in cells demonstrates excellent kinome-wide selectivity. Differential anticancer activity...
Abstract Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and implicated other solid tumours. minimally expressed healthy tissues, making it potential therapeutic target. Unfortunately, as ligandless factor, brachyury has historically been considered undruggable. To investigate direct targeting by small molecules, we determine structure human both alone complex with DNA. The structures provide insights into DNA binding context...
Protein tyrosine sulfation is a post-translational modification best known for regulating extracellular protein-protein interactions. Tyrosine catalysed by two Golgi-resident enzymes termed tyrosylprotein sulfotransferases (TPSTs) 1 and 2, which transfer sulfate from the cofactor PAPS (3'-phosphoadenosine 5'-phosphosulfate) to context-dependent in protein substrate. A lack of quantitative assays has hampered development chemical biology approaches identification small-molecule inhibitors...
Inhibitors based on a 3-acylaminoindazole scaffold were synthesized to yield potent dual AAK1/BMP2K inhibitors. Optimization furnished small molecule chemical probe (SGC-AAK1-1, 25) that is and selective for over other NAK family members, demonstrates narrow activity in kinome-wide screen, functionally active cells. This inhibitor represents one of the best available tools study functions AAK1 BMP2K.
We describe the design of a set inhibitors to investigate relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both vitro using cell target engagement assays. The most potent further kinome-wide screen demonstrating narrow spectrum profiles. While we observed direct correlation EGFR antiproliferative effects on chordoma, GAK inhibition appeared have only limited effect.
Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (
The calcium/calmodulin-dependent protein kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. deregulation of CAMKK2 is linked several diseases, suggesting the utility inhibitors for oncological, metabolic inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor CAMKK2, potently inhibits significant number other kinases. Through an analysis literature public databases, have identified...