Fluzoparib
(Synonyms: 氟唑帕利; SHR3162; Fuzuloparib) 目录号 : GC62121
Fluzoparib (SHR3162, HS10160) is a potent Poly (ADP-ribose) polymerase (PARP) inhibitor that shows anti-tumor activity.
Cas No.:1358715-18-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- SDS (Safety Data Sheet)
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Fluzoparib (SHR3162, HS10160) is a potent Poly (ADP-ribose) polymerase (PARP) inhibitor that shows anti-tumor activity.
All four NSCLC cell lines (A549, H460, H1299, and PC9) shows decreased viability upon exposure to fluzoparib, and the effect is time and dose dependent. Fluzoparib acts synergistically to inhibit cell growth and promote apoptosis among lung cancer cells.[2]
An H460 cell xenograft mouse model is established to study the in vivo effects of fluzoparib and RT on tumor growth and survival. Treatment with RT + fluzoparib more effectively delayed tumor growth than treatment with either RT or fluzoparib individually. When combined with RT, fluzoparib conferres a significant survival benefit with no evidence of toxicity.[2]
[1] Ye Han, et al. Am J Cancer Res. 2019 Mar 1;9(3):608-618. [2] Jing Luo, et al. J Cancer Res Clin Oncol. 2020 Mar;146(3):721-737.
| Cas No. | 1358715-18-0 | SDF | |
| 别名 | 氟唑帕利; SHR3162; Fuzuloparib | ||
| 分子式 | C22H16F4N6O2 | 分子量 | 472.4 |
| 溶解度 | DMSO : 50 mg/mL (105.84 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1169 mL | 10.5843 mL | 21.1685 mL |
| 5 mM | 0.4234 mL | 2.1169 mL | 4.2337 mL |
| 10 mM | 0.2117 mL | 1.0584 mL | 2.1169 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer
Clin Cancer Res 2021 May 1;27(9):2452-2458.PMID:33558426DOI:10.1158/1078-0432.CCR-20-3546.
Purpose: Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of Fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer. Patients and methods: This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1. Results: A total of 113 patients were enrolled and received at least one dose of Fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5-18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6-78.2] and 70.8% (95% CI, 61.5-79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3-13.9) and 10.3 months (95% CI, 9.2-12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2-96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred. Conclusions: Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, Fluzoparib might be a novel treatment option for this population.
Chidamide Reverses Fluzoparib Resistance in Triple-Negative Breast Cancer Cells
Front Oncol 2022 Feb 18;12:819714.PMID:35251986DOI:10.3389/fonc.2022.819714.
Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance is a new challenge for antitumor therapy. The purpose of this study was to investigate the reversal effects of chidamide on Fluzoparib resistance, a PARPi, and its mechanism of action. A fluzoparib-resistant triple-negative breast cancer (TNBC) cell line was constructed, and the effects of chidamide and Fluzoparib on drug-resistant cells were studied in vitro and in vivo. The effects of these drugs on cell proliferation, migration, invasiveness, the cell cycle, and apoptosis were detected using an MTT assay, wound-healing and transwell invasion assays, and flow cytometry. Bioinformatics was used to identify hub drug resistance genes and Western blots were used to assess the expression of PARP, RAD51, MRE11, cleaved Caspase9, and P-CDK1. Xenograft models were established to analyze the effects of these drugs on nude mice. In vivo results showed that chidamide combined with Fluzoparib significantly inhibited the proliferation, migration, and invasiveness of drug-resistant cells and restored Fluzoparib sensitivity to drug-resistant cells. The combination of chidamide and Fluzoparib significantly inhibited the expression of the hub drug resistance genes RAD51 and MRE11, arrested the cell cycle at the G2/M phase, and induced cell apoptosis. The findings of this work show that chidamide combined with Fluzoparib has good antineoplastic activity and reverses TNBC cell resistance to fluzoparil by reducing the expression levels of RAD51 and MRE11.
Fuzuloparib Maintenance Therapy in Patients With Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial
J Clin Oncol 2022 Aug 1;40(22):2436-2446.PMID:35404684DOI:10.1200/JCO.21.01511.
Purpose: This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly Fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer. Patients and methods: Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation. Results: Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count). Conclusion: Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.
Pharmacologic characterization of Fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials
Cancer Sci 2019 Mar;110(3):1064-1075.PMID:30663191DOI: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.
A phase I study of Fluzoparib tablet formulation, an oral PARP inhibitor: effect of food on the pharmacokinetics and metabolism after oral dosing in healthy Chinese volunteers
Expert Opin Drug Metab Toxicol 2021 Apr;17(4):503-508.PMID:33535835DOI:10.1080/17425255.2021.1881480.
Objective: To evaluate the effect of food on the pharmacokinetics (PK) of Fluzoparib capsule. Methods: PK data were obtained after Fluzoparib treatment in a crossover design study. Single-dose Fluzoparib (120 mg) was administered under fasted and fed conditions to 16 healthy subjects. Metabolism and transformation Fluzoparib were analyzed by liquid chromatograph-tandem mass spectrometry in the first period. Safety was also assessed. Results: The absorption rate of Fluzoparib was slower in the fed group (tmax delayed by 3 h), and peak exposure (Cmax) of Fluzoparib in plasma decreased by 19.8% (p < 0.05) compared with the fasted group. The area under the curve (AUC) of Fluzoparib was not statistically different between the fasted and fed conditions. The 90% confidence intervals for the Cmax and AUC0-∞ were 69.77-92.24% and 84.88-102.26%, respectively. Five, seven, and five Fluzoparib metabolites were isolated from plasma, urine, and feces samples, respectively. Most treatment-emergent adverse events were grade I or II. Conclusions: The presence of food decreased the absorption rate and peak exposure time of Fluzoparib; however, the AUC did not significantly change compared with the fasted condition. Therefore, oral administration does not alter the efficacy and safety profile of Fluzoparib.