Strategies employed for the development of PARP inhibitors

Canan, S; Maegley, K; Curtin, N

doi:10.1007/978-1-61779-270-0_28

Strategies employed for the development of PARP inhibitors

Lookup NU author(s): Professor Nicola Curtin ORCiD

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Abstract

This chapter describes the approaches taken in the development of the first PARP inhibitor to enter clinical trial, AG-014699, in 2003. We describe the general principles of crystal-based drug design, the purification and crystallisation 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 is described with reference to its advantages and disadvantages.