A5012318825- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Catalytic Cross-Coupling Reactions
- Chemical synthesis and alkaloids
- Organoboron and organosilicon chemistry
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Advanced Synthetic Organic Chemistry
- Galectins and Cancer Biology
- Asymmetric Synthesis and Catalysis
- Radical Photochemical Reactions
- Quinazolinone synthesis and applications
- Pneumocystis jirovecii pneumonia detection and treatment
- Synthetic Organic Chemistry Methods
Age UK
2021-2024
GlaxoSmithKline (United Kingdom)
2016-2021
University of Strathclyde
2015-2018
GlaxoSmithKline (India)
2017
Glasgow Life
2015
University of Hertfordshire
2015
The Chan-Evans-Lam reaction is a valuable C-N bond forming process. However, aryl boronic acid pinacol (BPin) ester reagents can be difficult coupling partners that often deliver low yields, in particular reactions with amines. Herein, we report effective conditions for the amination of BPin alkyl and A mixed MeCN/EtOH solvent system was found to enable formation using amines while EtOH not required
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. four BET bromodomains—BRD2, BRD3, BRD4, BRDT—each contain two modules. inhibition is a potential therapy for various cancers immunoinflammatory diseases, but few reported inhibitors show selectivity within the family. Inhibitors with first or second are desired to aid investigation biological function these domains. Focused library screening identified series...
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design characterisation GSK215, potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on binder VHL E3 ligase known inhibitor VS-4718. X-ray crystallography revealed molecular basis highly cooperative FAK-GSK215-VHL ternary complex, GSK215 showed differentiated in-vitro...
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that co-opt the cell's natural proteasomal degradation mechanisms to degrade undesired proteins. A challenge associated with PROTACs is time and resource-intensive optimization; thus, development of high-throughput platforms for their synthesis biological evaluation required. In this study, we establish an ultra-high-throughput experimentation (ultraHTE) platform PROTAC synthesis, followed by direct addition crude...
The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization this series leading to identification superior suitable vivo studies.
Functionalised biaryl phenols can be rapidly accessed <italic>via</italic> one-pot Suzuki–Miyaura cross-coupling, chemoselective control of boron solution speciation, and oxidation.
The regioselective synthesis of 3-aminoimidazo[1,2-a]pyrimidines via triflic anhydride mediated amide activation and intramolecular cyclisation is reported. nature the added pyridine base allows access to both regioisomers from a simple common precursor. method tolerates range functional groups provides novel heterocyclic scaffolds.
Abstract Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design characterisation GSK215, potent, selective, FAK‐degrading Proteolysis Targeting Chimera (PROTAC) based on binder VHL E3 ligase known inhibitor VS‐4718. X‐ray crystallography revealed molecular basis highly cooperative FAK‐GSK215‐VHL ternary complex, GSK215 showed differentiated...
Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation cell surface, driving activation adaptive immune responses. In cancer, overtrimming mature antigenic peptides reduce cytotoxic T-cell responses, and ERAP1 generate self-antigenic contribute to autoimmune cellular Therefore, modulation activity has potential therapeutic indications cancer immunotherapy in...
Targeted protein degradation is an emerging new strategy for the modulation of intracellular levels with applications in chemical biology and drug discovery. One approach to enable this redirect ubiquitin-proteasome system mark degrade target proteins interest (POIs) through use proteolysis targeting chimeras (PROTACs). Although great progress has been made enabling PROTACs as a platform, there are still limited number E3 ligases that have employed PROTAC design. Herein we report novel...
Abstract The reaction conditions for Chan—Evans—Lam amination of alkyl and aryl amines with boronic acid pinacol esters are revised.