Pharmacologic characterization of fluzoparib, a novel poly(ADP‐ribose) polymerase inhibitor undergoing clinical trials

• Published in: Cancer science Vol. 110; no. 3; pp. 1064 - 1075
• Main Authors: Wang, Lei, Yang, Changyong, Xie, Chengying, Jiang, Jiahua, Gao, Mingzhao, Fu, Li, Li, Yun, Bao, Xubin, Fu, Haoyu, Lou, Liguang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2019; John Wiley and Sons Inc
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Breast cancer; Cancer therapies; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Clinical trials; Clinical Trials as Topic; Cytotoxicity; Defects; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA damage; DNA repair; DNA Repair - drug effects; Drug dosages; Enzymatic activity; Enzymes; FDA approval; Female; fluzoparib; Gastric cancer; Homologous recombination; Homologous recombination repair; Humans; Hypoxia; Kinases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Original; Ovarian cancer; Paclitaxel; Pharmaceuticals; pharmacokinetics; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Rats; Rats, Sprague-Dawley; Ribose; Software; toxicity; Xenograft Model Antitumor Assays - methods; Xenografts; United States > US; China; toxicity; pharmacokinetics; fluzoparib; antitumor activity; poly(ADP-ribose) polymerase
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13947

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 showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR‐deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor 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. Fluzoparib, a novel and potent PARP inhibitor undergoing phase II clinical trials, displays favorable pharmacokinetic properties and superior in vivo antitumor activity compared with olaparib. For the first time, we discover that fluzoparib in combination with apatinib and paclitaxel elicits significantly improved antitumor responses without extra toxicity. Based on this finding, a phase I study has been initiated.