Overview of PARP inhibitor design and optimization

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme and the founding member of the PARP family of enzymes. Inhibition of PARP-1 has been the focus of drug discovery groups for over three decades in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, inflammation, diabetes and most importantly cancer. Despite the great therapeutic potential for this target and over a decade of clinical studies, only recently have PARP inhibitors made headway in late stage clinical trials. After many tribulations, recent results from several PARP inhibitors in Phase II clinical trials for cancer therapy have reinvigorated the field. This chapter is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target for oncology and explain the genesis of the PARP inhibitor pharmacophore. In addition, this chapter will provide the optimization paradigms for each of the PARP inhibitors currently in clinical trials, analyzing some of the differentiating factors for the clinical compounds and a brief mention of the current clinical progress for each inhibitor.