Alzheimer disease amyloid -peptide (A) is generated via proteolytic processing of the -amyloid precursor protein by -and ␥-secretase. ␥-Secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal antiinflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid A 42 and concomitantly increase the levels of the rather benign A 38 . Here we show that A 42 and A 38 generation occur independently from each other. The amount of A 42 produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of ␥-secretase, appeared to correlate with the respective age of onset in patients. However, A 38 levels did not show a negative correlation with the age of onset. Modulation of ␥-secretase activity by sulindac sulfide reduced A 42 in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of A 42 or only rather subtle effects. Strikingly, even the mutations that showed no effect on A 42 levels allowed a robust increase of A 38 upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase A 42 and to decrease A 38 . For mutants that predominantly produce A 42 , the ability of fenofibrate to further increase A 42 levels became diminished, whereas A 38 levels were altered to varying extents for all mutants analyzed. Thus, we conclude that A 38 and A 42 production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the A 42 -lowering capacity of ␥-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to ␥-secretase modulators.Alzheimer disease is the most abundant form of dementia, and increasing numbers of patients are to be expected in the near future. Amyloid -peptide (A) 5 is a central player in the disease pathology. Originally it was purified as the building block of the disease-defining amyloid plaques. Now it is becoming clear that amyloid plaques are probably not the major neurotoxic entity in the disease rather this is an assembly of soluble oligomeric A species (1). These assemblies initiate the so-called amyloid cascade and finally induce abnormal phosphorylation of tau and subsequent formation of paired helical filaments (2). A is generated by proteolytic processing of the -amyloid precursor protein (APP). Two proteases, -secretase and ␥-secretase, perform the cleavages on the N and C termini of the A domain, respectively (3). -Secretase is a conventional aspartyl protease, whereas ␥-secretase i...
The aim of scaffold hopping is to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule. Scaffold hopping is a central task of modern medicinal chemistry requiring a multitude of techniques, which are discussed in this article. Their application has led to several molecules with chemically completely different core structures, and yet binding to the same receptor. Computational approaches for scaffold hopping highlight the challenges of the field that are still unsolved.:
Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of γ-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.
Antibodies SZ-cis-39C11 and SZ-trans-28F8, which were elicited in response to N-aryl-3-methoxyphenyl proline derivatives, catalyze the [2,3]-sigmatropic rearrangement of allylic sulfoxides to sulfenates. Reduction of the sulfenates with dithiothreitol in situ yields allylic alcohols as the final product. The antibodies achieve rate accelerations in the range 10(2)-10(3) over background and exhibit distinctive hapten-dependent substrate specificity and enantio- and diastereoselectivity. Of particular note is the effective chirality transfer from the sulfoxide center to the product alcohol in the SZ-cis-39C11-catalyzed conversion of (Z)-2-(4-methoxyphenyl)-but-2-en-1-yl 4-nitrophenyl sulfoxide. These properties can be contrasted with those of bovine serum albumin (BSA) which accelerates the same reactions to a comparable extent but does not discriminate between substrate isomers. Partitioning of substrate from aqueous solution into the less polar environment of the protein pocket can account for much of the observed rate enhancement, whereas specific conformational constraints programmed by the haptens must orient the flexible substrate within the induced antibody-combining sites so as to favor certain reaction pathways over others. These studies thus expand the scope of antibody catalysis to an important new class of pericyclic reactions and illustrate how medium effects can be exploited together with conformational constraint to control reactivity and selectivity.
Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-γ-Glu-γ-secretase-inhibitor 13a.
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