Strategies Employed for the Development of PARP Inhibitors

This chapter describes the approaches taken in the development of the first PARP inhibitor to enter clinical trial, rucaparib (now called Rubraca), in 2003. We describe the general principles of crystal-based drug design, the purification and crystallization of the PARP-1 catalytic domain and how th...

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Bibliographic Details
Published inMethods in molecular biology (Clifton, N.J.) Vol. 1608; p. 271
Main Authors Canan, Stacie, Maegley, Karen, Curtin, Nicola J
Format Journal Article
LanguageEnglish
Published United States 2017
Subjects
Animals
Catalytic Domain
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Indoles - chemistry
Indoles - pharmacology
Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors - chemistry
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
PARP activity assay
PARP1
Protein purification
Crystallography
PARP inhibitors
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Summary:This chapter describes the approaches taken in the development of the first PARP inhibitor to enter clinical trial, rucaparib (now called Rubraca), in 2003. We describe the general principles of crystal-based drug design, the purification and crystallization of the PARP-1 catalytic domain and how this was used to develop highly potent PARP inhibitors, based on the nicotinamide pharmacophore. Several methods have been used to determine the inhibitory potency in cell-free and whole cell assays, each described with reference to its advantages and disadvantages.
ISSN:1940-6029
DOI:10.1007/978-1-4939-6993-7_18