A5022973468- Computational Drug Discovery Methods
- Microtubule and mitosis dynamics
- Protein Kinase Regulation and GTPase Signaling
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Wnt/β-catenin signaling in development and cancer
- Cholinesterase and Neurodegenerative Diseases
- Protein Degradation and Inhibitors
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- SARS-CoV-2 and COVID-19 Research
- Bioinformatics and Genomic Networks
- Cytokine Signaling Pathways and Interactions
- Calcium signaling and nucleotide metabolism
- interferon and immune responses
- Peptidase Inhibition and Analysis
- Microbial Natural Products and Biosynthesis
- Chemical Synthesis and Analysis
- Phosphodiesterase function and regulation
- Advanced Breast Cancer Therapies
- Drug Transport and Resistance Mechanisms
- Cancer-related gene regulation
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
- Melanoma and MAPK Pathways
University of North Carolina at Chapel Hill
2016-2025
Joint Center for Structural Genomics
2017-2024
International Drug Development
2023
University of North Carolina Health Care
2019-2021
Communities In Schools of Orange County
2020
Stanford University
2014-2018
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...
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...
Allosteric regulation of the pseudokinase TRIB1 reveals therapeutic potential kinase 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.
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...
3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility animal models due to their poor pharmacokinetic properties. While developing analogues with reduced intrinsic clearance potential for sustained exposure mice, we discovered that phase II conjugation by GST enzymes was a major metabolic transformation hepatocytes. A protocol codosing ethacrynic acid, covalent reversible...
Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency demonstrated vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed confirmation excellent in-cell lead compound, 40, another promising analogue, 46. Evaluation the pharmacokinetic (PK) profiles these two revealed that both are well tolerated systemically orally bioavailable. Coupled its...
Bryostatin 1 (henceforth bryostatin) is in clinical trials for the treatment of Alzheimer's disease and HIV/AIDS eradication. It also a preclinical lead cancer immunotherapy other therapeutic indications. Yet nothing known about conformation bryostatin bound to its protein kinase C (PKC) target membrane microenvironment. As result, efforts design more efficacious, better tolerated, or synthetically accessible ligands have been limited structures that do not include PKC effects influence...
The pyrimidine core has been utilized extensively to construct kinase inhibitors, including eight FDA-approved drugs. Because the hinge-binding motif is accommodated by many human kinases, kinome-wide selectivity of resultant molecules can be poor. This liability was seen as an advantage since it well tolerated understudied kinases. We hypothesized that nonexemplified aminopyrimidines bearing side chains from well-annotated pyrimidine-based inhibitors with off-target activity on kinases...
Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that expressed mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 TTBK2 have been delineated. While efforts devoted to characterizing impact of inhibition diseases like Alzheimer's disease amyotrophic lateral sclerosis, has less explored. serves a critical function during cilia assembly. Given biological importance these kinases, we designed targeted library from which identified several...
Specificity is a limiting factor when using small-molecule inhibitors to study protein kinase signalling. Since inhibitor-resistant mutants (i.e., drug-resistant alleles) remain active in the presence of inhibitor, they facilitate validation on-target effects. By combining an mutant with mass spectrometry-based phosphoproteomics, we previously devised systematic strategy for reliable identification and CSNK2 substrates. In this study, use same evaluate selectivity CX-4945, clinical stage...
Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of potent selective small molecule probe targeting CDKL5 could enable illumination roles normal development as well diseases where it has become aberrant due to mutation. prepared analogs...
RNA sequencing and genetic data support spleen tyrosine kinase (SYK) high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the by binding doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction p-ITAM SYK-tSH2 enables phosphorylation. Since...
Cilia are cellular signaling hubs. Given that human kinases central regulators of signaling, it is not surprising key players in cilia biology. In fact, many modulate ciliogenesis, which the generation cilia, and distinct ciliary pathways. Several these understudied with few publications dedicated to interrogation their function. Recent efforts develop chemical probes for members cyclin-dependent kinase like (CDKL), never mitosis gene A (NIMA) related (NEK), tau tubulin (TTBK) families...
The pyrazolo[1,5-a]pyrimidine scaffold is a promising to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of 1,2,4-triazole group substitute key amide for binding present in many inhibitors. Crystallographic evidence demonstrates that replaces forming hydrogen bonds Lys68 water molecule buried ATP-binding pocket. This isosteric replacement improves potency metabolic stability at cost solubility. Optimization...
Novel treatments for neurodegenerative disorders are in high demand. It is imperative that new protein targets be identified to address this need. Characterization and validation of nascent can accomplished very effectively using highly specific potent chemical probes. Human induced pluripotent stem cells (hiPSCs) provide a relevant platform testing compounds disease cell types. However, many recent studies utilizing have focused on neuronal cells. In study, we used hiPSC-derived...
From a designed library of indolyl pyrimidinamines, we identified highly potent and cell-active chemical probe (17) that inhibits phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). Comprehensive evaluation inhibitor selectivity confirmed this PIKfyve demonstrates excellent kinome-wide selectivity. A structurally related pyrimidinamine (30) was characterized as negative control lacks inhibitory activity exhibits exquisite when profiled broadly. Chemical 17 disrupts multiple phases the...