A5015133572- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Fungal and yeast genetics research
- Cholinesterase and Neurodegenerative Diseases
- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- Genomics and Chromatin Dynamics
- Neuroscience and Neuropharmacology Research
- Endoplasmic Reticulum Stress and Disease
- Crystallization and Solubility Studies
- Click Chemistry and Applications
- Dementia and Cognitive Impairment Research
- X-ray Diffraction in Crystallography
- Neurological diseases and metabolism
- Microbial Metabolic Engineering and Bioproduction
- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- Photosynthetic Processes and Mechanisms
- Biofuel production and bioconversion
- Health Systems, Economic Evaluations, Quality of Life
- Statistical Methods in Clinical Trials
- Synthesis and Catalytic Reactions
Bristol-Myers Squibb (United States)
2009-2020
GlaxoSmithKline (United States)
2016
Teva Pharmaceuticals (United States)
2016
Eisai (United States)
2016
Yale University
2016
Pfizer (United States)
2016
Hartford Financial Services (United States)
2016
Biohaven Pharmaceuticals (United States)
2016
Bristol-Myers Squibb (Germany)
2008-2015
Wilmington University
2000-2001
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for treatment Alzheimer's disease, we investigated series carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, brain efficacy after oral dosing led discovery 4 (BMS-708163). Compound is (Aβ40 IC50 = 0.30 nM), demonstrating 193-fold selectivity against Notch. Oral administration significantly reduced Aβ40 levels sustained periods in...
Pantothenic acid and β-alanine are metabolic intermediates in coenzyme A biosynthesis. Using a functional screen the yeast Saccharomyces cerevisiae, putative amine oxidase, encoded by FMS1, was found to be rate-limiting for pantothenic Overexpression ofFMS1 caused excess excreted into medium, whereas deletion mutants required or growth. Furthermore, genes ECM31 andYIL145c, which both have structural homology of bacterial pathway, were also The FMS1 FAD-containing oxidases its role...
The Saccharomyces cerevisiae protein kinase Dbf2 carries out an essential function in late mitosis, and its activity is cell-cycle regulated around anaphase/telophase. We have isolated SDB25, a high copy suppressor of temperature-sensitive dbf2 mutants, genetic analysis suggests that the two proteins may parallel pathways mitosis. SDB25 encodes p40, previously characterized substrate potent inhibitor Cdc28 activity. Sdb25 phosphoprotein, immunoprecipitates histone H1 CDC28-dependent....
The ability to counterselect, as well select for, a genetic marker has numerous applications in microbial genetics. Described here is the use of 5-fluoroanthranilic acid for counterselection TRP1, commonly used yeast Saccharomyces cerevisiae. Counterselection using involves antimetabolism by enzymes tryptophan biosynthetic pathway, such that trp1, trp3, trp4 or trp5 strains, which lack required conversion anthranilic tryptophan, are resistant acid. Commonly procedures, selection loss...
Deactivation of the B cyclin kinase (Cdc28/Clb) drives telophase to G1 cell cycle transition. Here we investigate one control pathways that contributes deactivation, involving cycle-regulated production cdk inhibitor Sic1. We show timing SIC1 expression depends on transcription factor Swi5, and Swi5-dependent begins during telophase. In contrast related Ace2, which can also induce expression, is not active The functional consequence Swi5-regulated in vivo both sic1Δ swi5Δ strains have...
ABSTRACTThe DBF2 gene of the budding yeast Saccharomyces cerevisiae encodes a cell cycle-regulated protein kinase that plays an important role in telophase/G1 transition. As component multisubunit CCR4 transcriptional complex, is also involved regulation expression. We have found MOB1, essential required for late mitotic event cycle, genetically and physically interacts with DBF2. binds MOB1 vivo can bind it vitro absence other proteins. expression cycle regulated, its peaking slightly...
A hallmark of Alzheimer's disease (AD) pathology is the accumulation brain amyloid <i>β</i>-peptide (A<i>β</i>), generated by <i>γ</i>-secretase-mediated cleavage precursor protein (APP). Therefore, <i>γ</i>-secretase inhibitors (GSIs) may lower A<i>β</i> and offer a potential new approach to treat AD. As also cleaves Notch proteins, GSIs can have undesirable effects due interference with signaling. Avagacestat (BMS-708163) GSI developed for selective inhibition APP over cleavage. was...
The amyloid-β (Aβ) peptide, which likely plays a key role in Alzheimer disease, is derived from the precursor protein (APP) through consecutive proteolytic cleavages by β-site APP-cleaving enzyme and γ-secretase. Unexpectedly γ-secretase inhibitors can increase secretion of Aβ peptides under some circumstances. This "Aβ rise" phenomenon, same inhibitor causing an at low concentrations but inhibition higher concentrations, has been widely observed. Here we show that rise depends on...
This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part 6041-membered solid-phase library. The synthesis multiple follow-up solid- solution-phase libraries facilitated original micromolar hit into single-digit nanomolar in both radioligand binding cell-based functional assay formats. X-ray structure representative inhibitors bound to revealed number key ligand:protein...
The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a <i>γ</i>-secretase modulator (GSM), were tested in healthy young elderly volunteers after single multiple doses. BMS-932481 was orally absorbed, showed dose proportionality administration, had approximately 3-fold accumulation dosing. High-fat/caloric meals doubled the <i>C</i><sub>max</sub> area under curve prolonged <i>T</i><sub>max</sub> by 1.5 hours. Consistent with preclinical pharmacology GSMs, decreased...
Abstract The amino acid β-alanine is an intermediate in pantothenic (vitamin B5) and coenzyme A (CoA) biosynthesis. In contrast to bacteria, yeast derive the required for production via polyamine metabolism, mediated by four SPE genes FAD-dependent amine oxidase encoded FMS1. Because oxidases generally produce aldehyde derivatives of compounds, we propose that additional aldehyde-dehydrogenase-mediated step make from precursor aldehyde, 3-aminopropanal. This study presents evidence closely...
We have shown previously that the Swi5 transcription factor regulates expression of SIC1 Cdk inhibitor in late mitosis. This suggests might control other genes with roles ending identified a gene Swi5-binding site promoter encoded protein high homology to Pcl2, cyclin-like associates Pho85. gene,PCL9, is indeed regulated by M phase, only cyclin known be expressed at this point cell cycle. The Pcl9 associated Pho85-dependent kinase activity, and unstable peak levels occurring phase. PCL2...
By targeting the flap backbone of BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved inhibitory activity over lead compound 1. The cocrystal structure bound to site indicated two hydrogen-bond interactions between dimethylisoxazole and threonine 72 glutamine 73 flap. Incorporation substitution onto related carboxamide series led pyrazine-carboxamide 26 as a very potent inhibitor (IC50 < 1 nM). This demonstrated robust brain Aβ...
Saccharomyces cerevisiae dbf4 and cdc7 cell cycle mutants block initiation of DNA synthesis (i.e., are iDS mutants) at 37 degrees C arrest the with a 1C content. Surprisingly, certain strains divide their chromatin C. We found that activation Cdc28 mitotic protein kinase Dbf2 occurred correct relative timing respect to each other observed division unreplicated chromatin. Furthermore, depended on functional spindle. Therefore, nuclear resembled normal mitosis, suggesting S. commits M phase in...
The dbf3 mutation was originally obtained In a screen for DNA synthesis mutants with cell cycle phenotype in the budding yeast Saccharomyces cerevlslae. We have now isolated DBFS gene and found It to be an essential ORF of 7239 nucleotldes, potentially encoding large protein 268 kDa. also allele-specific high copy number suppressor dbf3-1 allele, encoded by known SSB1 gene, member Hsp70 family heat shock proteins. sequence Dbf3 is 58% identical over 2300 amino acid residues predicted from...
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from patients, genetic analysis mutations that early onset forms AD, preclinical studies. Based this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors an attractive therapeutic approach for because cleavage APP by BACE1 required form Abeta. In study, three potent...
The amyloid-<i>β</i> peptide (A<i>β</i>)—in particular, the 42–amino acid form, A<i>β</i>1-42—is thought to play a key role in pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming inhibit A<i>β</i> synthesis or increase clearance have entered clinical trials, including <i>γ</i>-secretase inhibitors, anti-A<i>β</i> antibodies, and precursor protein cleaving enzyme inhibitors. A unique class small molecules, modulators (GSMs), selectively reduce A<i>β</i>1-42...