A5105423244- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Advanced biosensing and bioanalysis techniques
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- RNA Interference and Gene Delivery
- Histone Deacetylase Inhibitors Research
- Cystic Fibrosis Research Advances
- HIV Research and Treatment
- Cancer therapeutics and mechanisms
- Pharmacological Receptor Mechanisms and Effects
- Cancer-related Molecular Pathways
- Pancreatic function and diabetes
- Virology and Viral Diseases
- CAR-T cell therapy research
- Pharmacogenetics and Drug Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Ion Transport and Channel Regulation
- Polyamine Metabolism and Applications
- Synthesis and Catalytic Reactions
University of North Carolina at Chapel Hill
2016-2025
University of North Carolina Health Care
2025
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...
Peptides have historically been underutilized for covalent inhibitor discovery, despite their unique abilities to interact with protein surfaces and interfaces. This is in part due a lack of methods screening identifying peptide ligands. Here, we report method identify cyclic inhibitors mRNA display. We combine co- post-translational library diversification strategies create libraries reactive dehydroalanines (Dhas), which employ selections against two model targets. The most potent hits...
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics any infection. CHIKV nonstructural protein 2 (nsP2), which contains cysteine protease domain, essential viral replication, making it an attractive target drug discovery campaign. Here, we optimized nsP2 (nsP2pro) biochemical assay screening of 6,120-compound cysteine-directed covalent fragment...
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,...
To better understand the contribution of methyl-lysine (Kme) binding proteins to various disease states, we recently developed and reported discovery 1 (UNC3866), a chemical probe that targets two families Kme proteins, CBX CDY chromodomains, with selectivity for CBX4 -7. The was enabled in part by use molecular dynamics simulations performed CBX7 its endogenous substrate. Herein, describe design, synthesis, structure-activity relationship studies led development provide support our model...
Chromatin regulatory complexes localize to specific sites via recognition of posttranslational modifications (PTMs) on N-terminal tails histone proteins (e.g., methylation, acetylation, and phosphorylation). Molecular modified histones is mediated by "reader" protein subunits. The recruited govern processes such as gene transcription, DNA replication, chromatin remodeling. Dysregulation consequent downstream effects have been associated with a variety disease states, leading an interest in...
MAGE proteins are cancer testis antigens (CTAs) that characterized by highly conserved homology domains (MHDs) and increasingly being found to play pivotal roles in promoting aggressive types. MAGE-A4, particular, increases DNA damage tolerance chemoresistance a variety of cancers stabilizing the E3-ligase RAD18 trans-lesion synthesis (TLS). Inhibition MAGE-A4:RAD18 axis could sensitize cells chemotherapeutics like platinating agents. We use an mRNA display thioether cyclized peptides...
A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer neurodegenerative disease progression. To help understand the role of triple Tudor domain (3TD) its Kme reader, we first identify low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both TD2 TD3 binding sites. Further optimization leads to discovery UNC10013, covalent 3TD ligand targeting Cys385 SETDB1. UNC10013 potent with kinact/KI 1.0 × 106...
DNA-encoded library (DEL) technology has become a powerful tool in modern drug discovery. Fully harnessing its potential requires the use of advanced computational methodologies, which are often available only through proprietary software. This limitation restricts flexibility and accessibility for academic researchers small biotech companies, hindering growth technology. Here, we present DELi, an open-source DEL informatics platform designed design, NGS decoding calling, enrichment...
Chromatin structure and function, consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes 'read' these PTMs. High-quality chemical probes can block reader functions proteins involved regulation are important tools to improve our understanding pathways dynamics. Insight into the intricate system PTMs...
The interpretation of histone post-translational modifications (PTMs), specifically lysine methylation, by specific classes "reader" proteins marks an important aspect epigenetic control gene expression. Methyl-lysine (Kme) readers often regulate expression patterns through the recognition a Kme PTM while participating in or recruiting large protein complexes that contain enzymatic chromatin remodeling activity. Understanding composition these Kme-reader-containing can serve to further our...
Increased expression and hyperactivation of the methyltransferase SET domain bifurcated 1 (SETDB1) are commonly observed in cancer central nervous system disorders. However, there currently no reported SETDB1-specific inhibitors literature, suggesting that this is a challenging target. Here, we disclose previously small-molecule ligand for SETDB1's triple tudor domain, (R,R)-59, unexpectedly able to increase SETDB1 activity both vitro cells. Specifically, (R,R)-59 promotes SETDB1-mediated...
Plant homeodomain finger protein 1 (PHF1) is an accessory component of the gene silencing complex polycomb repressive 2 and recognizes active chromatin mark, trimethylated lysine 36 histone H3 (H3K36me3). In addition to its role in transcriptional regulation, PHF1 has been implicated as a driver endometrial stromal sarcoma fibromyxoid tumors. We report discovery characterization UNC6641, peptidomimetic antagonist Tudor domain which was optimized through silico modeling incorporation...
Multivalent binding is an efficient means to enhance the affinity and specificity of chemical probes targeting multidomain proteins in order study their function role disease. While theory multivalent straightforward, physical structural characterization bivalent encounters multiple technical difficulties. We present a case where combination experimental techniques computational simulations was used comprehensively characterize structure–affinity relationships for series Bromosporine-based...
Calcium and integrin binding protein 1 (CIB1) is an EF-hand-containing, small intracellular that has recently been implicated in cancer cell survival proliferation. In particular, CIB1 depletion significantly impairs tumor growth triple-negative breast (TNBC). Thus, a potentially attractive target for chemotherapy yet to be validated by chemical probe. To produce probe molecule the helix 10 (H10) pocket demonstrate it viable molecular intervention, we employed random peptide phage display...
Abstract Epigenetic modifications are involved in the onset, development, and maintenance of pain; however, precise epigenetic mechanism underlying pain regulation remains elusive. Here it is reported that factor chromodomain Y‐like (CDYL) crucial for processing. Selective knockout CDYL sensory neurons results decreased neuronal excitability nociception. Moreover, facilitates histone 3 lysine 27 trimethylation (H3K27me3) deposition at Kcnb1 intron region thus silencing voltage‐gated...
Methyl-lysine (Kme) reader domains are prevalent in chromatin regulatory proteins which bind post-translational modification sites to recruit repressive and activating factors; therefore, these play crucial roles cellular signaling epigenetic regulation. Proteins that contain Kme implicated various diseases, including cancer, making them attractive therapeutic targets for drug chemical probe discovery. Herein, we report on expanding the utility of a previously reported, Kme-focused...
New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in inflammation. The activation of IRE1α promotes its cytoplasmic kinase and RNase, resulting mRNA splicing X-box binding protein-1 (XBP-1s), a transcription factor required cytokine production. We tested whether RNase inhibition decreases production induced by exposure primary cultures homozygous F508del human bronchial...
The heterochromatin protein 1 (HP1) sub-family of CBX chromodomains are responsible for the recognition histone H3 lysine 9 tri-methyl (H3K9me3)-marked nucleosomal substrates through binding N-terminal chromodomain. These HP1 proteins, namely, CBX1 (HP1β), CBX3 (HP1γ), and CBX5 (HP1α), commonly associated with regions pericentric heterochromatin, but recent literature studies suggest that regulation by these proteins is likely more dynamic includes other loci. Importantly, there no chemical...
A promising drug target, SETDB1, is a dual Kme reader and methyltransferase, which has been implicated in cancer neurodegenerative disease progression. To help understand the role of triple Tudor domain (3TD) its reader, we first identified low micromolar small molecule ligand, UNC6535, occupies simultaneously both TD2 TD3 binding sites. Further optimization led to discovery UNC10013, covalent 3TD ligand targeting Cys385 SETDB1. UNC10013 potent with k
CHD1 is a chromodomain-helicase DNA-binding protein that preferentially recognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3). Genetic studies have established as synthetic lethal target in phosphatase tensin homologue (PTEN)-deficient cancers. Despite this attractive therapeutic link, no inhibitors or antagonists of been reported to date. Herein, we report the discovery UNC10142, first-in-class small molecule antagonist tandem chromodomains binds with an IC
Methyl-lysine reader p53 binding protein 1 (53BP1) is a central mediator of DNA break repair and associated with various human diseases, including cancer. Thus, high-quality 53BP1 chemical probes can aid in further understanding the role genome pathways. Herein, we utilized focused DNA-encoded library screening to identify novel hit compound UNC8531, which binds tandem Tudor domain (TTD) an IC
SUMMARY Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess biological roles putative drug targets. This approach capitalizes on advantages small molecule inhibitors while moving beyond restrictions traditional pharmacology. Herein we report a first-in-class degrader (UNC6852) that targets Polycomb Repressive Complex 2 (PRC2). UNC6852 contains EED226 derived ligand for VHL which bind WD40 aromatic cage EED CRL2...