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p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors, however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achieving potency and selectivity through targeting an inactive state of the kinases induced by a unique folded P-loop conformation. Using a rapid, systematic combinatorial synthetic approach, we identified compound 93 (SR-318) with excellent potency and selectivity for p38α/β which potently inhibited the TNF-α release in whole blood. SR-318 presents therefore a potent and selective type-II inhibitor of p38α/β, that can be used as a chemical probe for targeting this particular inactive state of these two p38 isoforms.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Chinese Hamster Ovary (CHO) cells are used for industrial production of protein-based therapeutics (i.e. 'biologics'). Here we describe a method for combining systems-level kinetic models with a synth...
Drug of abuse (DOA) consumption is a growing problem worldwide, particularly with increasing numbers of new psychoactive substances (NPS) entering the drug market. Generally, little information on the...
Heparan sulfate (HS) and dermatan sulfate (DS) are l-iduronic acid containing glycosaminoglycans (GAGs) which are implicated in a number of biological processes and conditions including cancer and vir...
Synthetic gene circuits emerge from iterative design-build-test cycles. Most commonly, the time-limiting step is the circuit construction process. Here, we present a hierarchical cloning scheme based ...
We propose a fast iterative image reconstruction algorithm for normal, short-scan, and super-short-scan fan-beam computed tomography (CT), which aims at iterative reconstruction for low-dose and few-v...
This is set as prospective clinical trial to correlate histologically and radiologically the performance of four different bone grafts (synthetic hydroxyapatite alone, synthetic hydroxyapa...
This research study aims to improve the standard exam called Focused Assessment with Sonography in Trauma (FAST). The FAST exam is an ultrasound test used to identify an abdominal bleed. T...
Peripherally Inserted Central Catheter (PICC) and port-a-cath (PAC) are the most commonly medical devices used for the administration of chemotherapy. Placement of these devices via centr...
This study will evaluate the safe and effective dose conversion from synthetic T4 therapy to Armour Thyroid therapy in participants who are euthyroid on a stable dose of synthetic T4.
This study evaluates the clinical ease of use of the Femoral Antegrade Starting Tool (FAST).
An iterative questionnaire designed to measure consensus among individual responses. In the classic Delphi approach, there is no interaction between responder and interviewer.
A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber.
Skeletal muscle fibers characterized by their expression of the Type II MYOSIN HEAVY CHAIN isoforms which have high ATPase activity and effect several other functional properties - shortening velocity, power output, rate of tension redevelopment. Several fast types have been identified.
Any situation where an animal or human is trained to respond differentially to two stimuli (e.g., approach and avoidance) under reward and punishment conditions and subsequently trained under reversed reward values (i.e., the approach which was previously rewarded is punished and vice versa).
Cell surface proteins that bind amino acids and trigger changes which influence the behavior of cells. Glutamate receptors are the most common receptors for fast excitatory synaptic transmission in the vertebrate central nervous system, and GAMMA-AMINOBUTYRIC ACID and glycine receptors are the most common receptors for fast inhibition.
Adhd Anorexia Depression Dyslexia Mental Health Psychiatry Schizophrenia Stress Mental health, although not being as obvious as physical health, is very important, causing great unhappiness to those affected, causing add...