A5058061121- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Synthetic Organic Chemistry Methods
- SARS-CoV-2 and COVID-19 Research
- Advancements in Semiconductor Devices and Circuit Design
- Multiple Myeloma Research and Treatments
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Hydrogen embrittlement and corrosion behaviors in metals
- Cell Adhesion Molecules Research
- CAR-T cell therapy research
- Click Chemistry and Applications
- Epigenetics and DNA Methylation
- Semiconductor materials and devices
- DNA and Nucleic Acid Chemistry
- Radiation Effects in Electronics
- Synthesis and biological activity
- Cancer-related gene regulation
- Cyclopropane Reaction Mechanisms
- Synthesis and Catalytic Reactions
R&D Systems (United States)
2025
Novartis (Switzerland)
2007
University of Sussex
2007
Novartis Institutes for BioMedical Research
2007
The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among first reported inhibitors was peptidomimetic α-ketoamide 13b, whose cocrystal structure with paved way for multiple lead-finding studies. We established structure-activity relationships 13b series modifying residues at P1', P3, and P4 sites. Guided structures, we reduced P1' substituent size better fill pocket added fluorine pyridone ring, enabling new hydrogen bond Gln189 in P3....
SARS-CoV-2 is the causative agent behind COVID-19 pandemic. The main protease (Mpro, 3CLpro) of a key enzyme that processes polyproteins translated from viral RNA. Mpro therefore an attractive target for design inhibitors block replication. We report diastereomeric resolution previously designed α-ketoamide inhibitor 13b. pure (S,S,S)-diastereomer, 13b-K, displays IC50 120 nM against and EC50 values 0.8-3.4 μM antiviral activity in different cell types. Crystal structures have been...
CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric driven by fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to C-terminal activation domain DUX4. CDS rapidly develops resistance chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that requires P300/CBP induce histone H3 acetylation, activate its targets, drive oncogenesis. describe synthetic route selective potent inhibitor named...
PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall vitro degradation antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor vivo pharmacokinetic profile. To further demonstrate PG...
Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess test potential exit vectors on the inhibitor, ISOX-DUAL. Candidate Degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. panel CRBN-recruiting thalidomide-based unable induce or degradation target proteins. High-resolution protein co-crystal structures an unexpected interaction between thalidomide moiety Trp81...
p300 and CBP are paralogous epigenetic regulators promising therapeutic targets for which TPD offers the potential to achieve paralog-selective degradation.
Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative diseases. These molecules have non-occupancy based, sub-stoichiometric mechanism of action which results in removal target proteins from cells, presenting opportunities interrogate intervene pathogenic signalling. Identifying chemical starting points for PROTACs remains largely empirical process...
Visualizing and manipulating proteins in live cells is crucial for studying complex biological processes. Self-labelling protein (SLP) tags such as HaloTag SNAP-tag can be fused to genes of interest allow labelling cells. Limitations including size the tag suboptimal fitness reactivity motivate development improved tools enable rapid, specific stable labelling. We present BromoCatch, a novel SLP platform based on small ~13 kDa bromodomain (BD) engineered with nucleophilic cysteine covalent...
Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess test potential exit vectors on the inhibitor, ISOX-DUAL. Candidate degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. panel CRBN-recruiting thalidomide-based degraders unable induce or degradation target proteins. High-resolution protein cocrystal structures an unexpected interaction between thalidomide moiety...
In addition to the therapeutic applicability of targeted protein degradation (TPD), modality also harbors unique properties that enable development innovative chemical biology tools interrogate complex biology. TPD offers an all-chemical strategy capable potent, durable, selective, reversible, and time-resolved control levels a given target in both vitro vivo contexts. These are particularly well-suited for enabling precise perturbation gene understand its biology, identify...
A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro compounds and range substituted alkenes. This chemistry offers attractive route to would otherwise be difficult prepare, have very useful application as precursors variety heterocyclic entities.
(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, its cocrystal structure was determined complex with first BRD4 compared that known small-molecule probe. At 1 μM concentration, (+)-JD1 able to inhibit c-Myc, key driver cancer an indirect target BRD4.
Supporting degrader discovery programs in scale and scope: facile access to multi-hundred-gram quantities of the common E3 ligase ligands.
TC AC 28, 6-(1H-Indol-4-yl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetic acid methyl ester, has been synthesized on a near-gram scale in seven steps with notable improvements the reported poor-yielding last two enabling this key chemical probe compound to be available for researchers.
A much improved synthesis, in significantly higher overall yield, for this important chemical probe is reported. Problematic steps have been revisited, closely examined and rectified.
Abstract CREB-binding protein (CBP, CREBBP, KAT3A) and E1A-binding (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain catalyzes the H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such enhancers promoters. Transcription factors associate with stretches of H3K27ac marks (known ‘super-enhancer’ elements) result in gene transcription ultimately establishes...
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