Fluzoparib

Fluzoparib (SHR3162) is a potent and orally active PARP1 inhibitor (IC₅₀=1.46±0.72 nM, a cell-free enzymatic assay) with superior antitumor activity. Fluzoparib selectively inhibits the proliferation of homologous recombination repair (HR)-deficient cells, and sensitizes both HR-deficient and HR-proficient cells to cytotoxic agents. Fluzoparib exhibits good pharmacokinetic properties in vivo and can be used for BRCA1/2-mutant relapsed ovarian cancer research^[1]. In Vitro: Fluzoparib (30?μM; 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^[1].
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^[1].
Fluzoparib (10?μM; 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 cells?cells^[1].
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 0.51?μM, 1.57?μM, 0.053?μM, 1.57?μM, and 1.43?μM, respectively. The IC₅₀ values for HR-proficient cells (V-C8#13-5 and UWB1.289 BRCA1) are both >10?μM^[1].
In Vivo: Fluzoparib (oral gavage; 0.3, 1, or 3?mg/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 2?hours. In contrast, concentrations of fluzoparib in tumor remains at high levels even at 24?hours after dosing (57.9?ng/g , 39.3 ng/g, and 85.6?ng/g for doses of 0.3, 1, and 3?mg/kg, respectively)^[1].
Fluzoparib (oral gavage; 30 mg/kg; 21 days) apparently inhibits the growth of tumor with an inhibition rate of 59% (day 21) at 30?mg/kg, and it does not cause significant loss of body weight in Nude mice bearing?MDA-MB-436 ?(BRCA1-deficient)?model^[1].
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^[1].