Pharmacologic Characterization of Fluzoparib, a Novel Poly(ADP‐ribose) polymerase (PARP) Inhibitor Undergoing Clinical Trials

Abstract

Poly(ADP‐ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first‐in‐class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA‐mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR‐3162), a novel, potent and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double‐strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)‐deficient cells. Fluzoparib preferentially inhibited the proliferation of HR‐deficient cells and sensitized both HR‐deficient and HR‐proficient cells to cytotoxic drugs. Notably, fluzoparib exhibited good pharmacokinetic properties, favorable toxicity profile and superior anti‐tumor activity in HR‐deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved anti‐tumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.

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