Chapter title |
High-Throughput Colorimetric Assay for Identifying PARP-1 Inhibitors Using a Large Small-Molecule Collection
|
---|---|
Chapter number | 19 |
Book title |
Poly(ADP-Ribose) Polymerase
|
Published in |
Methods in molecular biology, July 2017
|
DOI | 10.1007/978-1-4939-6993-7_19 |
Pubmed ID | |
Book ISBNs |
978-1-4939-6992-0, 978-1-4939-6993-7
|
Authors |
Kotova, Elena, Tulin, Alexei V., Elena Kotova, Alexei V. Tulin |
Abstract |
Poly(ADP-ribose)polymerase 1 (PARP-1) protein became a popular target for treatment of several types of cancer. A number of PARP-1 inhibitors are currently in clinical trials. Most of them were designed competitors with NAD for a binding site on PARP-1 molecule. This strategy resulted in a discovery of mainly nucleotide-like PARP-1 inhibitors, which may target not only PARP-1 but also other pathways involving NAD and other nucleotides. Many cancer types demonstrate rapid development of resistance to NAD-like PARP-1 inhibitors. Thus, identification and characterization of new small molecules inhibit PARP-1 with high specificity and efficacy is important for the clinical research. We have proposed a new approach to screen libraries for new PARP-1 inhibitors based on histone H4-dependent PARP-1 activation. Beside identification of NAD competitors in a small molecules collection, this approach allows finding other classes of PARP-1 inhibitors that specifically disrupt H4-based PARP-1 activation or arrest inactive allosteric conformation of PARP-1. Here, we present an adaptation of this approach for a large-scale high-throughput screen. |
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Student > Master | 1 | 25% |
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Chemistry | 1 | 25% |
Unknown | 3 | 75% |