A5020818396- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Phagocytosis and Immune Regulation
- PARP inhibition in cancer therapy
- Galectins and Cancer Biology
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Axon Guidance and Neuronal Signaling
- Cancer Treatment and Pharmacology
- Microtubule and mitosis dynamics
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- DNA Repair Mechanisms
- CAR-T cell therapy research
- Angiogenesis and VEGF in Cancer
- Melanoma and MAPK Pathways
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- Lysosomal Storage Disorders Research
- DNA and Nucleic Acid Chemistry
- Cancer-related gene regulation
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Quinazolinone synthesis and applications
AstraZeneca (United Kingdom)
2016-2025
AstraZeneca (Brazil)
2024-2025
MRC Protein Phosphorylation and Ubiquitylation Unit
2013-2023
University of Dundee
2006-2023
Medical Research Council
2014-2023
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and therefore target interest for immunooncology. Nonselective HPK1 inhibitors may affect other components activation, blunting beneficial impact enhanced activity that results from inhibition itself. Here, we report discovery pyrazine carboxamide their optimization through structure-based drug design to afford highly selective inhibitor, compound 24 (AZ3246). This induces IL-2 secretion...
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some failed combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP lack selectivity PARP1 over PARP2 and other 16 family members, we hypothesized that this could contribute toxicity. Recent literature has demonstrated inhibition PARP1–DNA trapping are...
E3 ubiquitin ligases engage their substrates via ‘degrons’ - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and hard to drug conventional means, alternative strategies needed target them in diseases, peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide Cdc20, substrate-recognition subunit...
Many phosphorylation signal transduction pathways in the eukaryotic cell are modulated by posttranslational modification of specific serines/threonines with N-acetylglucosamine (O-GlcNAc). Levels O-GlcNAc on key proteins regulate biological processes as diverse cycle, insulin signaling, and protein degradation. The two enzymes involved this dynamic abundant transferase O-GlcNAcase. Structural data have recently revealed that O-GlcNAcase possesses an active site significant structural...
Programmed cell death ligand-1 (PD-L1) expression levels in patient tumor samples have proven clinical utility across various cancer types. Several independently developed PD-L1 immunohistochemical (IHC) predictive assays are commercially available. Published studies using the VENTANA (SP263) Assay, (SP142) Dako IHC 22C3 pharmDx assay, 28-8 and laboratory-developed tests utilizing E1L3N antibody (Cell Signaling Technology), demonstrated differing of staining between assays, resulting...
DNA-PK is a key component within the DNA damage response, as it responsible for recognizing and repairing double-strand breaks (DSBs) via non-homologous end joining. Historically has been challenging to identify inhibitors of catalytic subunit (DNA-PKcs) with good selectivity versus structurally related PI3 (lipid) PI3K-related protein kinases. We screened our corporate collection DNA-PKcs kinase selectivity, identifying compound 1. Optimization focused on further improving while physical...
With a resurgence in interest covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery alkynyl benzoxazine and dihydroquinazoline reaction with cysteine. Their utility alternative electrophilic warheads for chemical biological probes drug molecules demonstrated through site-selective protein modification incorporation into kinase scaffolds. A potent...
PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of single-strand breaks by PARP-1's F1 and F2 domains via process further domain assembly activation the catalytic (CAT); synthesis attachment poly(ADP-ribose) (PAR) chains protein sidechains then signals for repair components. A component transmission signal HD subdomain CAT, which alone bridges between assembled DNA-binding active site ART CAT. Here we present study isolated CAT...
O-GlcNAcylation is an essential, dynamic and inducible post-translational glycosylation of cytosolic proteins in metazoa can show interplay with protein phosphorylation. Inhibition OGA (O-GlcNAcase), the enzyme that removes O-GlcNAc from O-GlcNAcylated proteins, a useful strategy to probe role this modification range cellular processes. In present study, we report rational design evaluation GlcNAcstatins, family potent, competitive selective inhibitors human OGA. Kinetic experiments...
Maintaining genome stability in the germline is thought to be an evolutionarily ancient role of p53 family. The sole Caenorhabditis elegans family member CEP-1 required for apoptosis induction meiotic, late-stage pachytene germ cells response DNA damage and meiotic recombination failure. In unbiased genetic screen negative regulators CEP-1, we found that increased activation C. ERK orthologue MPK-1, resulting from either loss lip-1 phosphatase or let-60 Ras, results enhanced cep-1–dependent...
Modification of cellular proteins with O-GlcNAc (O-linked N-acetylglucosamine) competes protein phosphorylation and regulates a plethora processes. O-GlcNAcylation is orchestrated by two opposing enzymes, transferase OGA (O-GlcNAcase or β-N-acetylglucosaminidase), which recognize their target via as yet unidentified mechanisms. In the present study, we uncovered first insights into mechanism substrate recognition human OGA. The structure novel bacterial orthologue reveals putative...
Inhibitors of OGT (O-GlcNAc transferase) are valuable tools to study the cell biology protein O-GlcNAcylation. We report bisubstrate-linked inhibitors (goblins) in which acceptor serine peptide VTPVSTA is covalently linked UDP, eliminating GlcNAc pyranoside ring. Goblin1 co-crystallizes with OGT, revealing an ordered C₃ linker and retained substrate-binding modes, binds enzyme micromolar affinity, inhibiting glycosyltransfer on substrates.
The chitinase-like proteins YKL-39 (chitinase 3-like-2) and YKL-40 3-like-1) are highly expressed in a number of human cells independent their origin (mesenchymal, epithelial or haemapoietic). Elevated serum levels have been associated with negative outcome diseases ranging from cancer to inflammation asthma. expression has osteoarthritis. However, despite the reported association disease, physiological pathological role these is still very poorly understood. Although homologous two family...
While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by application targeted tyrosine kinase inhibitors capable inhibiting KIT-driven proliferation, diverse mutations to this drive resistance established therapies. Here we describe identification potent pan-KIT mutant that can be dosed without being limited tolerability issues seen with multitargeted agents. This effort focused on and optimization an existing scaffold through use structure-based design....
ATAD2 is an epigenetic bromodomain-containing target which overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have described the literature, their cellular activity proved to be underwhelming. In this work, we describe identification of novel series by high throughput screening, confirmation bromodomain region site action, optimization campaign undertaken improve potency, selectivity, permeability initial hit. The...
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to in vivo MAT2a tool inhibitor is discussed. structure-based drug discovery approach, aided relative binding free energy calculations, resulted AZ'9567 (21), a potent vitro with excellent preclinical pharmacokinetic properties. This showed selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both and vivo, providing further evidence support the utility inhibitors...
Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family RING finger E3 ubiquitin ligases, has been demonstrated to play central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via ubiquitin-mediated protein modulation. Thus, inhibition ligase activity can lead immune therapeutic potential immuno-oncology. Herein, we describe discovery...
Posttranslational modification of metazoan nucleocytoplasmic proteins with N-acetylglucosamine (O-GlcNAc) is essential, dynamic, and inducible can compete protein phosphorylation in signal transduction. Inhibitors O-GlcNAcase, the enzyme removing O-GlcNAc, are useful tools for studying role O-GlcNAc a range cellular processes. We report discovery nanomolar OGA inhibitors that up to 900,000-fold selective over related lysosomal hexosaminidases. When applied at concentrations on live cells,...
Protein O-GlcNAcylation is an essential reversible posttranslational modification in higher eukaryotes. O-GlcNAc addition and removal catalyzed by transferase O-GlcNAcase, respectively. We report the molecular details of interaction a bacterial O-GlcNAcase homolog with three different synthetic glycopeptides derived from characterized sites human proteome. Strikingly, peptides bind conserved substrate binding groove similar orientation conformation. In to extensive contacts sugar, recognizes...
Abstract Yersinia species cause zoonotic infections, including enterocolitis and plague. Here we studied ruckeri antifeeding prophage 18 (Afp18), the toxin component of phage tail-derived protein translocation system Afp, which causes enteric redmouth disease in salmonid fish species. show that microinjection glycosyltransferase domain Afp18 G into zebrafish embryos blocks cytokinesis, actin-dependent motility cell blebbing, eventually abrogating gastrulation. In ZF4 cells, depolymerizes...