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

Lei Wang; Changyong Yang; Chengying Xie; Jiahua Jiang; Mingzhao Gao; Li Fu; Yun Li; Xubin Bao; Liguang Lou

doi:10.1111/cas.13947

journal article Open Access Feb 19, 2019

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

Lei Wang

Changyong Yang Chengying Xie Jiahua Jiang Mingzhao Gao Li Fu

Yun Li

Xubin Bao Liguang Lou

Cancer Science Vol. 110 No. 3 pp. 1064-1075 · Wiley

View at Publisher Save 10.1111/cas.13947

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 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.

Topics

No keywords indexed for this article. Browse by subject →

References

26

[1]

10.1038/nrc2812

[2]

10.1073/pnas.1405005111

[3]

10.1038/nrm1963

[4]

10.1038/nature03443

[5]

10.1038/nature03445

[6]

10.1038/bjc.2016.67

[7]

10.2147/dddt.s147726

[8]

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

Mansoor R. Mirza, Bradley J. Monk, Jørn Herrstedt et al.

New England Journal of Medicine 10.1056/nejmoa1611310

[9]

10.1016/s0140-6736(17)32440-6

[10]

10.1056/nejmoa0900212

[11]

10.1016/s1470-2045(17)30469-2

[12]

10.1007/s10637-012-9922-7

[13]

10.1016/j.critrevonc.2016.10.010

[14]

10.1093/annonc/mdv308

[15]

Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial

Yung-Jue Bang, Runsheng Xu, Keisho Chin et al.

The Lancet Oncology 10.1016/s1470-2045(17)30682-4

[16]

10.1016/j.molcel.2015.10.013

[17]

10.1016/j.canlet.2012.05.004

[18]

Dziadkowiec KN "PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting" Prz Menopauzalny (2016)

[19]

10.1016/j.molcel.2015.10.040

[20]

CHMP assessment report‐Lynparza.European Medicines Agency 2014.

[21]

10.1200/jco.2014.32.15_suppl.2025

[22]

Apatinib in treatment of refractory gastric cancer

Vicki Brower

The Lancet Oncology 10.1016/s1470-2045(16)00138-8

[23]

10.1016/j.jare.2017.06.006

[24]

10.1158/0008-5472.can-05-2119

[25]

10.1128/mcb.24.19.8504-8518.2004

[26]

10.1016/j.critrevonc.2017.04.006

Cited By

85

Fuzuloparib with or without apatinib in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations (FABULOUS): interim analysis of a multicentre, three-arm, open-label, randomised, phase 3 trial

Huiping Li, Quchang Ouyang · 2025

The Lancet Oncology

Overview of fuzuloparib in the treatment of ovarian cancer: background and future perspective

Ning Li, Qi Liu · 2022

Journal of Gynecologic Oncology

Fuzuloparib: First Approval

Arnold Lee · 2021

Drugs

Metrics

85

Citations

26

References

Details

Published: Feb 19, 2019
Vol/Issue: 110(3)
Pages: 1064-1075
License: View

Authors

L

Lei Wang