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Journal of biomolecular screening (1)
The Open Medicinal Chemistry Journal (1)
Ajello, Christopher W (1)
Andrianov, Vyacheslav (1)
BLASS, BENJAMIN E. (1)
CASSEL, JOEL A. (1)
Cassel, Joel A (1)
Cassel, Joel A. (1)
Chu, Guo-Hua (1)
DeHaven, Robert N (1)
Dolle, Roland E (1)
Gu, Minghua (1)
Le Bourdonnec, Bertrand (1)
Leister, Lara K (1)
McDonnell, Mark E. (1)
O’ Hare, Heather (1)
PAWLYK, AARON C. (1)
REITZ, ALLEN B. (1)
Reitz, Allen B. (1)
Sellitto, Ian (1)
Tuthill, Paul A (1)
Velvadapu, Venkata (1)
Year of Publication
Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function
McDonnell, Mark E.
Reitz, Allen B.
Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC6, ATG7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.
TDP-43; caspase activation; mixed inhibition
Development of a Novel Nonradiometric Assay for Nucleic Acid Binding to TDP-43 Suitable for High-Throughput Screening Using AlphaScreen® Technology
BLASS, BENJAMIN E.
REITZ, ALLEN B.
PAWLYK, AARON C.
Journal of biomolecular screening
TAR DNA binding protein 43 (TDP-43) is a nucleic acid binding protein that is associated with the pathology of cystic fibrosis and neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. We have developed a robust, quantitative, nonradiometric high-throughput assay measuring oligonucleotide binding to TDP-43 using AlphaScreen® technology. Biotinylated single-stranded TAR DNA (bt-TAR-32) and 6 TG repeats (bt-TG6) bound with high affinity to TDP-43, with KD values of 0.75 nM and 0.63 nM, respectively. Both oligonucleotides exhibited slow dissociation rates, with half-lives of 750 min for bt-TAR-32 and 150 min for bt-TG6. The affinities of unlabeled oligonucleotides, as determined by displacement of either bt-TAR-32 or bt-TG6, were consistent with previous reports of nucleic acid interactions with TDP-43, where increasing TG or UG repeats yield greater affinity. A diversity library of 7360 compounds was screened for inhibition of TDP-43 binding to bt-TAR-32, and a series of compounds was discovered with nascent SAR and IC50 values ranging from 100 nM to 10 μM. These compounds may prove to be useful biochemical tools to elucidate the function of TDP-43 and may lead to novel therapeutics for indications where the TDP-43 nucleic acid interaction is causal to the associated pathology.
TDP-43; AlphaScreen; TAR DNA; ALS; cystic fibrosis
Design and Synthesis of Imidazopyrimidine Derivatives as Potent iNOS Dimerization Inhibitors
Le Bourdonnec, Bertrand
Ajello, Christopher W
Leister, Lara K
Tuthill, Paul A
O’ Hare, Heather
DeHaven, Robert N
Dolle, Roland E
The Open Medicinal Chemistry Journal
A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.
Results 1-3 (3)
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