A5048521310- Protein Degradation and Inhibitors
- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Multiple Myeloma Research and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- Synthesis and Biological Evaluation
- Muscle Physiology and Disorders
- Virus-based gene therapy research
- Trypanosoma species research and implications
- Cancer Mechanisms and Therapy
- Fluorine in Organic Chemistry
- Synthesis and Reactions of Organic Compounds
- RNA modifications and cancer
- Nerve injury and regeneration
- Monoclonal and Polyclonal Antibodies Research
- DNA Repair Mechanisms
- Glycosylation and Glycoproteins Research
- Synthesis and biological activity
- Asymmetric Synthesis and Catalysis
Vertex Pharmaceuticals (United Kingdom)
2024
Roche (Switzerland)
2021-2023
University of Oxford
2011-2020
Stanford University
2015-2017
Stanford Medicine
2015
Genomics (United Kingdom)
2011-2013
Science Oxford
2012
Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers histone-acetylation code. Competitive inhibitors this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, discovery subtype-selective histone-bromodomain great importance. We identified 3,5-dimethylisoxazole moiety novel acetyl-lysine...
The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives develop potent inhibitors BET (bromodomain and extra terminal domain) family with good ligand efficiency. X-ray crystal structures most compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that phenol acetate lead showed strong...
Activity-based probes (ABPs) are widely used to monitor the activity of enzyme families in biological systems. Inferring from probe reactivity requires that reacts with at its active site; however, probe-labeling sites rarely verified. Here we present an enhanced chemoproteomic approach evaluate and deubiquitinase enzymes, using bioorthogonally tagged ABPs a sequential on-bead digestion protocol enhance identification sites. We confirm labeling catalytic Cys residues reveal unexpected...
Simple 1-substituted 5- and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over related bromodomain CBP. The reported were prepared from simple starting materials in two steps followed by separation regioisomers or regioselectively three steps.
Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present discovery of allosteric inhibitor 57, novel fourth-generation overcome EGFRC797S-mediated patients harboring activating EGFRL858R mutation. 57 exhibits an improved potency compared previous inhibitors. To our knowledge, is first that demonstrates robust tumor regression mutant EGFRL858R/C797S...
Alzheimer's Disease (AD) is the most widespread form of dementia, with one pathological hallmarks being formation neurofibrillary tangles (NFTs). These consist phosphorylated Tau fragments. Asparagine endopeptidase (AEP) a key cleaving enzyme that generates aggregation-prone Inhibition AEP to reduce level toxic fragment could represent promising therapeutic strategy. Here, we report first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors an irreversible binding...
The ammonium-directed olefinic epoxidations of a range differentially N-substituted cyclic allylic and homoallylic amines (derived from cyclopentene, cyclohexene, cycloheptene) have been investigated, the reaction kinetics analyzed. results these studies suggest that both ring size identity substituents on nitrogen are important in determining overall rate stereochemical outcome epoxidation reaction. In general, secondary or tertiary with nonsterically demanding superior to sterically their...
Abstract A range of isoxazole‐containing amino acids was synthesized that displaced acetyl‐lysine‐containing peptides from the BAZ2A, BRD4(1), and BRD9 bromodomains. Three these were incorporated into a histone H4‐mimicking peptide their affinity for BRD4(1) assessed. Affinities are comparable to those hyperacetylated cognate peptide, demonstrated dependence on position at which unnatural residue incorporated. An isoxazole‐based alkylating agent developed selectively alkylate cysteine...
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents treating a range cancers inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET ligand (OXFBD02) inhibits interactions BRD4(1) with RelA subunit NF-κB, in addition to histone H4. This shows promising profile screen NCI-60 panel but was rapidly metabolised (t
The Trypanosoma cruzi (T. cruzi) parasite is the cause of Chagas disease, a neglected disease endemic in South America. life cycle T. complex and includes transitions between distinct stages. This change phenotype (without genotype) could be controlled by epigenetic regulation, might involve bromodomain-containing factors 1-5 (TcBDF1-5). However, little known about function TcBDF1-5. Here we describe fragment-based approach to identify ligands for factor 3 (TcBDF3). We expressed soluble...
Abstract Purpose: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present a novel (Compound Ia) designed address limitations available BRAFi/MEKi. Experimental Design: The novel, penetrant, paradox breaker BRAFi comprehensively characterized vitro, ex vivo, and...
Abstract A range of isoxazole‐containing amino acids was synthesized that displaced acetyl‐lysine‐containing peptides from the BAZ2A, BRD4(1), and BRD9 bromodomains. Three these were incorporated into a histone H4‐mimicking peptide their affinity for BRD4(1) assessed. Affinities are comparable to those hyperacetylated cognate peptide, demonstrated dependence on position at which unnatural residue incorporated. An isoxazole‐based alkylating agent developed selectively alkylate cysteine...
Glycosylation is a ubiquitous modification of proteins, necessitating approaches for its visualization and characterization. Bioorthogonally tagged monosaccharides have been instrumental to this end, offering chemical view into the cell biology glycans. Understanding use such by cellular biosynthetic pathways has expanded their applicability in biology, instance through strategy Bioorthogonal Cell-specific Tagging Glycoproteins (BOCTAG). Here, we show that two azide-tagged analogues...
Glycosylation is a ubiquitous modification of proteins, necessitating approaches for its visualization and characterization. Bioorthogonally tagged monosaccharides have been instrumental to this end, offering chemical view into the cell biology glycans. Understanding use such by cellular biosynthetic pathways has expanded their applicability in biology, instance through strategy named Bio-Orthogonal Cell-specific TAgging Glycoproteins (BOCTAG). Here, we show that two azide-tagged analogues...
The Trypanosoma cruzi ( T. ) parasite is the cause of Chagas disease, a neglected disease endemic in South America. life cycle complex and includes transitions between distinct stages. This change phenotype (without genotype) could be controlled by epigenetic regulation, might involve bromodomain-containing factors 1-5 Tc BDF1-5). However, little known about function BDF1-5. Here we describe fragment-based approach to identify ligands for factor 3 BDF3). We expressed soluble construct BDF3...