A5077673921- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- HIV Research and Treatment
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- HIV/AIDS drug development and treatment
- Cancer Mechanisms and Therapy
- Probiotics and Fermented Foods
- Genetics and Neurodevelopmental Disorders
- DNA Repair Mechanisms
- Multiple Myeloma Research and Treatments
- Gut microbiota and health
- Computational Drug Discovery Methods
- Genetics, Bioinformatics, and Biomedical Research
- CAR-T cell therapy research
- RNA Research and Splicing
- Chromatin Remodeling and Cancer
- Synthesis and Catalytic Reactions
University of North Carolina at Chapel Hill
2016-2025
UNC Lineberger Comprehensive Cancer Center
2022-2023
University of North Carolina Health Care
2018-2020
Communities In Schools of Orange County
2011-2014
Frenchay Hospital
2002
EZH2 or EZH1 is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation histone H3 lysine 27 (H3K27). The trimethylation H3K27 (H3K27me3) a transcriptionally post-translational modification. Overexpression and hypertrimethylation have been implicated in number cancers. Several selective inhibitors reported recently. Herein we disclose UNC1999, first orally bioavailable inhibitor has high vitro potency for wild-type mutant as well EZH1, closely related...
Abstract TANK binding kinase 1 (TBK1) is an important involved in the innate immune response. Here we discover that TBK1 hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia cancer cells. Tumors from patients with kidney VHL display elevated phosphorylation. Loss of via genetic ablation, pharmacologic inhibition, a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient cell growth, while leaving wild-type cells intact. depletion also significantly blunts...
Bivalent chemical degraders provide a catalytic route to selectively degrade disease-associated proteins. By linking target-specific ligands with E3 ubiquitin ligase recruiting ligands, these compounds facilitate targeted protein ubiquitination and degradation by the proteasome. Due complexity of this multistep mechanism, development effective degrader molecules remains difficult, lengthy, unpredictable process. Since are large heterobifunctional molecules, efficacy may be limited poor cell...
Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity NSD2 reported numerous cancers, efforts selectively inhibit the catalytic this protein with small molecules have been unsuccessful date. Here, we report development UNC8153, a novel NSD2-targeted degrader that potently and reduces cellular levels both H3K36me2 chromatin mark. UNC8153 contains...
Bivalent chemical degraders, otherwise known as proteolysis-targeting chimeras (PROTACs), have proven to be an efficient strategy for targeting overexpressed or mutated proteins in cancer. PROTACs provide alternative approach small-molecule inhibitors, which are restricted by occupancy-driven pharmacology, often resulting acquired inhibitor resistance via compensatory increases protein expression. Despite the advantages of bivalent they suboptimal physicochemical properties and optimization...
Dynamic combinatorial chemistry was utilized to identify a novel small molecule receptor, A2D, for asymmetric dimethyl arginine (aRMe2), which is post-translational modification (PTM) in proteins. It known play role number of diseases, including spinal muscular atrophy, leukemia, lymphoma, and breast cancer. The receptor exhibits 2.5–7.5-fold selectivity over the isomeric symmetric arginine, depending on surrounding sequence, with binding affinities low micromolar range. affinity A2D...
Abstract Polycomb group (PcG) proteins play critical roles in the epigenetic inheritance of cell fate. The Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to enforce gene silencing, but how transcriptional repression is propagated through mitotic divisions remains a key unresolved question. Using reversible tethering PcG ectopic sites mouse embryonic stem cells, here we show that can trigger Polycomb-dependent modifications. We find canonical (cPRC1), not variant...
Microbial β-glucuronidases (GUSs) cause severe gut toxicities that limit the efficacy of cancer drugs and other therapeutics. Selective inhibitors bacterial GUS have been shown to alleviate these side effects. Using structural chemical biology, mass spectrometry, cell-based assays, we establish piperazine-containing intercept glycosyl-enzyme catalytic intermediate retaining glycosyl hydrolases. We demonstrate piperazine-based compounds are substrate-dependent bind GUS-GlcA as a...
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present first antagonists that block protein–protein interaction between N-terminal PWWP domain H3K36me2. Using virtual screening experimental validation, identified small-molecule antagonist 3f, which binds NSD2-PWWP1 a Kd 3.4 μM abrogates histone...
Transcriptional silencing of HIV in CD4 T cells generates a reservoir latently infected that can reseed infection after interruption therapy. As such, these represent the principal barrier to curing infection, but little is known about their characteristics. To further our understanding molecular mechanisms latency, we characterized primary cell model latency which adopt heterogeneous transcriptional fates. In this model, observed stable, heritable state transmitted through division. Using...
Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting the may require combinatorial approaches. A Jurkat latency model screen IAPi combination partners demonstrated synergistic with bromodomain (BD) and extraterminal domain inhibitors (BETi). Mechanistic investigations CRISPR-CAS9 single-cell...
Lysine methylation is a key epigenetic mark, the dysregulation of which linked to many diseases. Small-molecule antagonism methyl-lysine (Kme) binding proteins that recognize such marks can improve our understanding these regulatory mechanisms and potentially validate Kme as drug-discovery targets. We previously reported discovery 1 (UNC1215), first potent selective small-molecule chemical probe reader protein, L3MBTL3, antagonizes mono- dimethyl-lysine reading function L3MBTL3. The design,...
Improving our understanding of the role chromatin regulators in initiation, development, and suppression cancer other devastating diseases is critical, as they are integral players regulating DNA integrity gene expression. Developing small molecule inhibitors for this target class with cellular activity a crucial step toward elucidating their specific functions. We specifically targeted damage response protein, 53BP1, which uses its tandem tudor domain to recognize histone H4 dimethylated on...
Regorafenib (Stivarga) is an oral small molecule kinase inhibitor used to treat metastatic colorectal cancer, hepatocellular carcinomas, and gastrointestinal stromal tumors. Diarrhea one of the most frequently observed adverse reactions associated with regorafenib. This toxicity may arise from reactivation inactive regorafenib-glucuronide regorafenib by gut microbial β-glucuronidase (GUS) enzymes in tract. We sought unravel molecular basis processing human intestinal GUS examine potential...
Efforts to develop strategies for small-molecule chemical probe discovery against the readers of methyl-lysine (Kme) post-translational modification have been met with limited success. Targeted disruption these protein-protein interactions via peptidomimetic inhibitor optimization is a promising alternative hit discovery; however, recognition identical peptide motifs by multiple Kme reader proteins presents unique challenge in development selective probes. These selectivity challenges are...
Abstract HIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents modulate host pathways which directly or indirectly facilitate reactivation. Inhibition of BET (bromo and extra-terminal domain) family member BRD4 reverses latency, but enthusiasm the use inhibitors in studies is tempered by concerns over inhibition other members dose-limiting toxicities oncology trials. Here we evaluated potential bivalent chemical degraders targeted as...
The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a network protein–protein interactions. Allosteric activation PRC2 binding methylated proteins to the embryonic ectoderm development (EED) aromatic cage essential for full catalytic activity, but details this regulation are not fully understood. EED's recognition product histone H3 lysine 27 trimethylation (H3K27me3), stimulates methyltransferase activity at adjacent nucleosomes leading H3K27me3 propagation and,...