生物活性

• 靶点

  FLT3 IC50:4.2nM

  FLT3 (ITD) IC50:1.1nM

• 描述The receptor tyrosine kinase of FLT3 is thought as implicating driver of acute myeloid leukemia (AML) due to the presence ratio of 30% for activated mutations found in AML patients. Quizartinib is the second-generation FLT3 inhibitor with binding affinity of Kd value of 1.6nM, and with IC50 values of 1.1nM, 4.2nM and 0.56nM for internal tandem duplications (ITDs) type or wild type of FLT3 autophosphorylation and MV4-11 cells proliferation, respectively. Quizartinib at concentration of 10μM demonstrated the highest affinity to FLT3 in a primary screen of 402 kinases. In a mice model orally administrated with Quizartinib at dose of 10mg/kg, a better absorption achieving at peak plasma concentration of 3.8μM within 2 hours was observed, and a concentration closing to its cellular IC50 value remained even after 24 hours. The peak concentration could be elevated to about 25μM at doses ranging from 0.1 to 100 mg/kg in a single-dose pattern. The highest plasma concentration achieved at dose ranging in 100-300mg/kg. When treated with Quizartinib at dose of 10mg/kg, 90% inhibition of FLT3 activity within 2 hours and 40% inhibition within 24 hour could be observed in a MV4-11 tumor xenograft model. Furthermore, no obvious signs of toxicity, including weight loss, was observed during 60-day period, suggesting the rapid and complete regression of this compound in tumor models. In primary AML cells, IC50 values of FLT3 autophosphorylation and cell viability were 2nM and 0.3nM, respectively, suggesting a well effect on cell survival . Quizartinib could significantly inhibit cell viability, cell growth, and induce cell apotosis in different cell lines with IC50 values ranging from 0.1 to 7248nM.

• 动物研究
  剂量	Nonhuman primates: 10 mg/kg - 200 mg/kg[3] (p.o.) Mice: 1 mg/kg, 10 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice Dose 10 mg/kg Administration p..o. Cmax 3.8 ± 0.4 μM Tmax 1.5 ± 0.9 h AUC0→24h 35 ± 4 μM·h