Clinical interest in poly(ADP-ribose) polymerase 1 (PARP-1) has increased over the past decade with the recognition of its roles in transcription regulation, DNA repair, epigenetic bookmarking, and chromatin restructuring. A number of PARP-1 inhibitors demonstrating clinical efficacy against tumors of various origins have emerged in recent years. These inhibitors have been essentially designed as nicotinamide adenine dinucleotide (NAD+) mimetics. However, because NAD+ is utilized by many enzymes other than PARP-1, NAD+ competitors tend to produce certain off-target effects. To overcome the limitation of NAD-like PARP-1 inhibitors, we have developed a new class of PARP-1 inhibitors that specifically targets the histone-dependent route of PARP-1 activation, a mechanism of activation that is unique to PARP-1. Novel histone-dependent inhibitors are highly specific for PARP-1 and demonstrate promising in vitro and in vivo efficacy against prostate and renal tumors. Our findings suggest that novel PARP-1 inhibitors have strong therapeutic potential for the treatment of urological tumors.
Urologic oncology. 2020 May 08 [Epub ahead of print]
Peter Makhov, Robert G Uzzo, Alexei V Tulin, Vladimir M Kolenko
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA., Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA., University of North Dakota, Grand Forks, ND. Electronic address: ., Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA. Electronic address: .