Rucaparib (AG014699) acetate is a highly effective oral inhibitor of PARP proteins, specifically targeting PARP-1, PARP-2, and PARP-3, with a Ki value of 1.4 nM for PARP1. Additionally, it exhibits inhibitory action on hexose-6-phosphate dehydrogenase (H6PD) to a moderate extent. Rucaparib acetate shows promise in the field of research for castration-resistant prostate cancer (CRPC). [1] [2] [3] [4]

PARP1:1.4 nM (Ki)

Rucaparib acetate (AG014699) is identified as a potential N-demethylation metabolite of AG14644, exhibiting cytotoxic effects with a half-maximal lethal concentration (LC50) of 5 μM in Capan-1 (BRCA2 mutant) cells and 100 nM in MX-1 (BRCA1 mutant) cells when applied at concentrations ranging from 0.1 to 100 μM over 24 hours. Its radio-sensitizing properties stem from the inhibition of NF-κB activation, a mechanism independent of single-strand break (SSB) repair inhibition. It specifically targets NF-κB pathways activated by DNA damage, thus overcoming the toxicity associated with traditional NF-κB inhibitors, without affecting other essential inflammatory functions. Additionally, Rucaparib acetate demonstrates a significant inhibition of PARP-1 activity, achieving a 97.1% reduction at a concentration of 1 μM in permeabilized D283Med cells.

Rucaparib (AG014699) acetate, in conjunction with AG14584, substantially enhances the toxicity of Temozolomide. Administration of 1 mg/kg of Rucaparib acetate markedly augments Temozolomide's effect in causing body weight loss. At a dosage of 0.1 mg/kg, Rucaparib acetate contributes to a significant 50% elevation in Temozolomide-induced tumor growth delay. Further, Rucaparib acetate dosages of 10 mg/kg intraperitoneally or 50 to 150 mg/kg orally, applied daily for five days weekly over a period of six weeks, demonstrate a pronounced inhibition of tumor growth, achieving one complete and two partial tumor regressions. The most substantial antitumor effect is observed with Rucaparib acetate at 150 mg/kg, administered orally either once or thrice per week for six weeks, which results in three complete tumor regressions. This compound notably amplifies the antitumor efficiency of Temozolomide, enabling complete and persistent tumor regressions in NB1691 and SHSY5Y xenografts.