title: Strategies employed for the development of PARP inhibitors.
abstract: This chapter describes the approaches taken in the development of the first PARP inhibitor to enter into clinical trial, AG-014699. We describe the general principles of crystal-based drug design, the purification, and crystallization of the PARP-1 catalytic domain, and how this approach was used to develop highly potent PARP inhibitors based on the nicotinamide pharmacophore. Several methods have been used to determine the inhibitory potency of designed inhibitors in cell-free and whole cell assays; each is described with reference to its advantages and disadvantages.
authors.affiliation: Celgene Research, San Diego, CA, USA.
authors.forename: Stacie
authors.initials: S
authors.lastname: Canan
authors.forename: Karen
authors.initials: K
authors.lastname: Maegley
authors.forename: Nicola
authors.initials: N
authors.lastname: Curtin
mesh_terms: D000818:Animals; D003461:Crystallography; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors