The basic goal of small-molecule screening is the identification of chemically 'interesting' starting points for elaboration towards a drug. A number of innovative approaches for pursuing this goal have evolved, and the right approach is dictated by the target class being pursued and the capabilities of the organization involved. A recent trend in high-throughput screening has been to place less emphasis on the number of data points that can be produced, and to focus instead on the quality of the data obtained. Several computational and technological advances have aided in the selection of compounds for screening and widened the variety of assay formats available for screening. The effect on the efficiency of the screening process is discussed.
A series of monosubstituted deoxy and deoxyfluoro 2,4-dinitrophenyl (DNP) β-d-glycopyranosides was synthesized and used to probe the mechanism of spontaneous β-glycoside hydrolysis. Their relative rates of hydrolysis followed the order 2-deoxy > 4-deoxy > 3-deoxy ≈ 6-deoxy > parent > 6-deoxy-6-fluoro > 3-deoxy-3-fluoro > 4-deoxy-4-fluoro > 2-deoxy-2-fluoro. Hammett correlations of the pH-independent hydrolysis rates of each of the 6-, 4-, 3-, and 2-position substituted glycosides with the σI value for the sugar ring substituent were linear (r = 0.95 to 0.999, ρI = −2.2 to −10.7), consistent with hydrolysis rates being largely dictated by field effects on an electron-deficient transition state. The relative rates of hydrolysis of the DNP glucosides can be rationalized on the basis of the stabilities of the oxocarbenium ion-like transition states, as predicted by the Kirkwood−Westheimer model. The primary determinant of the rate of hydrolysis within a series appears to be the field effect of the ring substituent on O5, the principal center of charge development at the transition state. Differences in the rates of hydrolysis between different series of hexopyranosides may not arise solely from field effects and likely also reflect differences in steric factors or solvation.
(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2-yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/ caspase-1 subfamily caspases. VRT-043198 exhibits 100-to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of interleukin (IL)-1 and IL-18, but it had little effect on the release of several other cytokines, including IL-1␣, tumor necrosis factor-␣, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis, and it did not affect the proliferation of activated primary T cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.The interleukin-converting enzyme (ICE), also known as caspase-1, is the cysteine protease that cleaves pro-interleukin (IL)-1 and pro-IL-18 to form the mature, active cytokines IL-1 and IL-18, respectively. IL-1 and IL-18 have important roles in the acute and chronic stages of inflammatory immune responses (for review, see Braddock and Quinn, 2004). IL-1 induces the expression of several mediators of immune cell response, including tumor necrosis factor (TNF)-␣, IL-6, cyclooxygenase-2, chemokines, Article, publication date, and citation information can be found at
The role of noncovalent interactions in the catalytic mechanism of the Agrobacterium faecalis beta-glucosidase was investigated by steady-state and pre-steady state kinetic analysis of the hydrolysis of a series of monosubstituted aryl glycosides, in which the hydroxyl groups on the glycone were substituted by hydrogen or fluorine. Contributions of each hydroxyl group to binding of these substrates at the ground state are relatively weak (interaction energies of 3.3 kJ/mol or smaller) but are much greater at the two transition states (glycosylation and deglycosylation). The strongest transition state interactions were at the 2 position (at least 18 and 22 kJ/mol for glycosylation and deglycosylation, respectively) with the interactions at the 3 and 6 positions contributing at least another 9 kJ/mol of binding energy at both transition states. The interaction at the 4 position is less crucial to transition state binding but important for stabilization of the glycosyl-enzyme intermediate. Comparison of observed rates with those for spontaneous hydrolysis of the same substrates provides evidence for oxocarbenium ion character at both transition states, that for deglycosylation apparently having the greater positive charge development at the anomeric center.
Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway
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