A5047858827- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- HIV Research and Treatment
- RNA Interference and Gene Delivery
- vaccines and immunoinformatics approaches
- Peptidase Inhibition and Analysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Histone Deacetylase Inhibitors Research
GlaxoSmithKline (United Kingdom)
2011-2022
GlaxoSmithKline (France)
2012
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by profound anti-inflammatory and antiproliferative effects a recently disclosed class BET compounds. While these compounds were discovered using phenotypic assays, here we present highly efficient alternative approach find new chemical...
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. possibility an ameliorated safety profile driven by significantly selective (>100-fold) inhibition a subset the eight bromodomains enticing, but challenging given close homology. Herein, we describe X-ray crystal structure-directed optimization novel weak fragment ligand with pan-second bromodomain (BD2) bias, to potent and highly BD2 inhibitors. A template hopping approach, enabled our parallel research...
Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of BET family proteins have shown profound efficacy in a number vitro phenotypic assays vivo pre-clinical models inflammation or oncology. A these progressed to clinic where pharmacology-driven adverse events been reported. To better understand contribution each their improve safety profile, selective are required. This article discloses profile GSK046, also known as iBET-BD2, highly...
Through regulation of the epigenome, bromodomain and extra terminal (BET) family proteins represent important therapeutic targets for treatment human disease. mimicking endogenous N-acetyl-lysine group disrupting protein–protein interaction between histone tails bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes medicinal chemistry strategy execution deliver an orally bioavailable tetrahydroquinoline (THQ) candidate....
A number of reports have recently been published describing the discovery and optimization bromo extraterminal inhibitors which are selective for second bromodomain (BD2); these include our own work toward GSK046 (3) GSK620 (5). This paper describes approach to mitigating genotoxicity risk by replacement acetamide functionality with a heterocyclic ring. was followed template-hopping hybridization approach, guided structure-based drug design, incorporate learnings from other BD2-selective...
The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. opportunity to identify with an improved safety profile by selective targeting a subset the eight bromodomains BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose identification potent and drug-like pan-BD2 such as pyrazole 23 (GSK809) furan 24 (GSK743) that were derived from pyrrole fragment...
Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock therapeutic benefits of antagonizing these proteins without eliciting toxicological aspects seen pan-BET inhibitors. While we have reported several distinct classes BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, describe lead optimization a further class highly soluble compounds based upon picolinamide...
Abstract A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed.