Quizartinib, Free Base **

产品名称：Quizartinib, Free Base
产品货号：LC  Q-4747
产品规格：10 MG
Quizartinib, also known as AC-220, is a second-generation FLT3 receptor tyrosine kinase inhibitor.
Quizartinib has high affinity for FLT3 in a binding assay (Kd = 1.6 nM) and is a potent inhibitor in cellular autophosphorylation assays (IC50 = 1.1 nM for FLT3-ITD and 4.2 nM for wt FLT3).  It inhibits the growth of human leukemia cell line MV4-11 (IC50 = 0.56 nM) which is FLT3 dependent and contains a homozygous FLT3-ITD mutation, and A375 cells (IC50 > 10,000 nM) which are not FLT3 dependent and contain an activating mutation in BRAF.  Quizartinib inhibits FLT3 activity in subcutaneous MV4-11 tumor xenografts.  Treatment with quizartinib at 10 mg/kg in MV4-11 tumor xenografts results in rapid and complete regression of tumors.  Quizartinib prolongs the survival of mice injected with MV4-11 cells in a dose-dependent manner.  Zarrinkar, P.P., et al.  "AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)."  Blood 114:  2984-2992 (2009).
Quizartinib inhibited the autophosphorylation of wt FLT3 and FLT3/ITD with IC50 values of 5 and 1 nM, respectively.  However, the cytotoxic effect of quizartinib was not exclusively dependent on inhibition of FLT3 autophosphorylation.  It depended on the clinical status of acute myoloid leukemia and FLT3-mutant allelic burden.  Relapsed samples and samples with a high mutant allelic burden were more sensitive to the cytotoxic effect from FLT3 inhibition by quizartinib compared with the samples obtained at diagnosis or those with a low mutant allelic burden.  Pratz, K.W., et al.  "FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML."  Blood 115:  1425-1432 (2010).
Quizartinib has demonstrated significant promise in early phases of clinical investigation with patients with acute myeloid leukemia (AML), and is now in more advanced clinical trials.  Fathi, A.T. and Chabner, B.A.  "FLT3 Inhibition as Therapy in Acute Myeloid Leukemia:  A Record of Trials and Tribulations."  The Oncologist 16:  1162-1174 (2011).
After intensive chemotherapy, plasma FLT3 ligand levels rose significantly in acute myeloid leukemia patients, which interfered with the cytotoxicity of quizartinib.  Sato, T., et al.  "FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo."  Blood 117:  3286-3293 (2011).
Related CAS numbers:  1132827-21-4 for the quizartinib dihydrochloride.
Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO at 200 mg/mL; very poorly soluble in ethanol; very poorly soluble in water; maximum solubility in plain water is estimated to be about 10-20 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.  Disposal:  A

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