Fluzoparib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Fluzoparib 是一种新型、有效、口服的 PARP 抑制剂，有可能用于治疗实体瘤。Fluzoparib 有效抑制 PARP1 酶活性，并在同源重组修复 (HR) 中诱导 DNA 双链断裂、G2/M 期停滞和细胞凋亡- 细胞缺陷。

fluzoparib is a novel, potent, and orally available inhibitor of PARP, potentially for the treatment of solid tumours.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.?In vitro experiments in NSCLC cell lines along with in vivo experiments using an NSCLC xenograft mouse model demonstrated the radiosensitization effect of fluzoparib.?The underlying mechanisms involved increased apoptosis, cell-cycle arrest, enhanced irradiation-induced DNA damage, and delayed DNA-damage repair.

Fluzoparib (30μM; 24 hour) increases the levels of γH2AX in a concentration‐dependent manner in both BRCA2‐deficient V‐C8 cells and?BRCA1‐deficient MDA‐MB‐436 cells, but not in BRCA‐proficient V‐C8#13‐5 cells.Fluzoparib (10?μM; 24 hour) increases levels of both pCDK1 and cyclin B, indicating activation of the G2/M checkpoint in MDA‐MB‐436 cells.Fluzoparib (10μM; 72 hour) increases the processing of caspase‐3, ‐8, and ‐9 concentration‐dependently, it induces G2/M arrest and apoptosis in HR‐deficient MDA‐MB‐436 cellscells.Fluzoparib is preferentially efficacious against HR‐deficient cells, such as BRCA1‐deficient (UWB1.289), MDA‐MB‐436, BRCA2‐deficient (V‐C8), BRCA1‐deficientBRCA2‐mutated (MX‐1) and BRCA1 hypermethylated (OVCAR‐8) cells with IC50 values of 0.51μM, 1.57?μM, 0.053 μM, 1.57μM, and 1.43μM, respectively. The IC50 values for HR‐proficient cells (V‐C8#13‐5 and UWB1.289 BRCA1) are both >10μM.

Fluzoparib (oral gavage; 0.3, 1, or 3mg/kg; single dose) exhibits a good pharmacokinetic profile in Female Balb/cA nude mice (5‐6 weeks old) mice bearing MDA‐MB‐436. After a single oral dose, fluzoparib is rapidly absorbed and rapidly cleared from blood at all dose levels; plasma concentrations of fluzoparib quickly reaches maximum within 2hours. In contrast, concentrations of fluzoparib in tumor remains at high levels even at 24 hours after dosing (57.9ng/g , 39.3 ng/g, and 85.6ng/g for doses of 0.3, 1, and 3mg/kg, respectively).Fluzoparib (oral gavage; 30 mg/kg; 21 days) apparently inhibits the growth of tumor with an inhibition rate of 59% (day 21) at 30mg/kg, and it does not cause significant loss of body weight in Nude mice bearing MDA‐MB‐436 (BRCA1‐deficient)model.Fluzoparib (3mg/kg) combines with Cisplatin, Paclitaxel, or Apatinib (oral gavage; BID; 21 days) causes growth inhibition with rates of 61.4%, 55.3%, and 72.8%, respectively.Fluzoparib, Cisplatin, and Apatinib combination or Fluzoparib, Paclitaxel, and Apatinib combination can cause growth inhibition with rates of 84.9% and 75.6% (day 21), respectively in vivo.The 2‐drug combination of Fluzoparib with cisplatin and The 3‐drug Fluzoparib, Cisplatin, and Apatinib combination lead to loss of body weight, whereas no apparent toxicity was observed in other combinations.

SHR3162, HS10160

Cell Cycle/DNA Damage

PARP

PARP

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1358715-18-0

472.4

C22H16F4N6O2

>98% (HPLC)

DMSO:94 mg/mL (198.98 mM)

C1CN2C(=NC(=N2)C(F)(F)F)CN1C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F

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(-20℃)

With Ice Pack

≥ 2 years