Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS Inhibitor.

Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS inhibitors. To date, KRAS inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding.

Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses.

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists.

In vivo activity of an azole series of CCR2 antagonists.

Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 14 [corrected] which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation. [Formula: see text]. [corrected].

Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist.

The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven-transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we describe an inverse agonist, GSK682753A, which selectively inhibited the constitutive activity of EBI2 with high potency and efficacy.

The characterization of a novel V1b antagonist lead series.

The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.

Identification of a sulfonamide series of CCR2 antagonists.

A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.

Using excised leaves to screen lucerne for salt tolerance: physiological and cytological evidence.

Salinity affects many physiological processes at all levels of plant structural organization. Being a physiologically and genetically complex trait, salinity tolerance implies a coordinated contribution of multiple mechanisms, making plant screening for salt tolerance extremely difficult. In this work, we show how the use of excised leaves can fulfill that task.

Multiple traits associated with salt tolerance in lucerne: revealing the underlying cellular mechanisms.

Salinity tolerance is a complex trait inferring the orchestrated regulation of a large number of physiological and biochemical processes at various levels of plant structural organisation. It remains to be answered which mechanisms and processes are crucial for salt tolerance in lucerne (Medicago sativa L.).

Postural context alters the stability of bimanual coordination by modulating the crossed excitability of corticospinal pathways.

The tendency for movements of the upper limbs to be drawn systematically toward one another and to follow similar spatiotemporal trajectories is well known. Although suppression of this tendency is integral to tasks of daily living, its exploitation may prove to be critical in the rehabilitation of acquired hemiplegias. In general, however, the task-related factors that determine the degree of coupling between the upper limbs and the mechanisms that mediate bilateral interactions between neural pathways projecting to the muscles of the arm and hand are not yet well understood.

Benzimidazole nitrogen-directed, regiocontrolled, lithiation of ferrocenyl- and phenyl-N-n-butylbenzimidazoles.

2-Ferrocenyl- and 2-phenyl-N-n-butylbenzimidazoles were synthesized to evaluate the influence of the benzimidazole functional group upon their directed lithiation. The regiochemistry of lithiation was studied, as well as the effect of stabilization of the lithiated species by diamine coordination using tetramethyl- ethylenediamine and (-)-sparteine. The lithiations were followed by reaction with a variety of electrophiles to give the disubstituted 2-ferrocenyl- and 2-phenyl-N-n-butylbenzimidazoles compounds.

Synthesis and structure of bifunctional N-alkylbenzimidazole phenylboronate derivatives.

N-Methyl and N-n-butyl-2-(2-boronophenyl)benzimidazoles are accessed from the corresponding mono-N-alkyl-ortho-phenylenediamines, either using a polyphosphoric acid-mediated cyclisation with ortho-bromobenzoic acid, or preferably using an Oxone-mediated cyclisation of the corresponding aldehyde, followed by a lithium-exchange and borylation sequence. The resulting boronic acids show unusual physical and chemical properties, as shown by 11B NMR and X-ray crystallography.

The effect of volition on the stability of bimanual coordination.

The authors investigated how the intention to passively perform a behavior and the intention to persist with a behavior impact upon the spatial and temporal properties of bimanual coordination. Participants (N = 30) were asked to perform a bimanual coordination task that demanded the continuous rhythmic extension-flexion of the wrists. The frequency of movement was scaled by an auditory metronome beat from 1.

Screening methods for waterlogging tolerance in lucerne: comparative analysis of waterlogging effects on chlorophyll fluorescence, photosynthesis, biomass and chlorophyll content.

Waterlogging is a serious environmental stress on lucerne (Medicago sativa) affecting its agronomic performance. To facilitate the breeding process, efficient tools to screen a population of lucerne cultivars are needed. In this study, a comparative analysis of waterlogging effects on leaf photosynthesis, pigment composition, PSII photochemistry, and plant growth characteristics was undertaken using four different lucerne cultivars (Aurora, Hunter River, L153 and Sequel HR).

Role of peripheral afference during acquisition of a complex coordination task.

It has long been supposed that the interference observed in certain patterns of coordination is mediated, at least in part, by peripheral afference from the moving limbs. We manipulated the level of afferent input, arising from movement of the opposite limb, during the acquisition of a complex coordination task. Participants learned to generate flexion and extension movements of the right wrist, of 75 degrees amplitude, that were a quarter cycle out of phase with a 1-Hz sinusoidal visual reference signal.

The acquisition of movement skills: practice enhances the dynamic stability of bimanual coordination.

During bimanual movements, two relatively stable "inherent" patterns of coordination (in-phase and anti-phase) are displayed (e.g., Kelso, Am.

Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria.

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries.

Neuromuscular-skeletal constraints upon the dynamics of unimanual and bimanual coordination.

In the first of three experiments, 11 participants generated pronation and supination movements of the forearm. in time with an auditory metronome. The metronome frequency was increased in eight steps (0.

Changes in posture alter the attentional demands of voluntary movement.

Two simple experiments reveal that the ease with which an action is performed by the neuromuscular-skeletal system determines the attentional resources devoted to the movement. Participants were required to perform a primary task, consisting of rhythmic flexion and extension movements of the index finger, while being paced by an auditory metronome, in one of two modes of coordination: flex on the beat or extend on the beat. Using a classical dual-task methodology, we demonstrated that the time taken to react to an unpredictable visual probe stimulus (the secondary task) by means of a pedal response was greater when the extension phase of the finger movement sequence was made on the beat of the metronome than when the flexion phase was coordinated with the beat.