生物活性

• 靶点	Ribonucleotide Reductase IC50:65nM

• 描述Clofarabine (CAFdA or CL-F-Ara-a) is a deoxyadenosine analogue compound that has been used in treatment for relapsed or refractory acute lymphoblastic leukemia (see https://www.fda.gov/). Clofarabine can inhibit DNA synthesis through both inhibition of ribonucleotide reductase activity and DNA polymeraseαactivity. The first, clofarabine is phosphorylated by deoxycytidine kinase to clofarabine triphosphate. Clofarabine triphosphate can compete with dATP for incorporation into A sites of the extending DNA strand catalyzed by both human DNA polymeraseα. The second, clofarabine triphosphate is a potent inhibitor of ribonucleotide reductase and thus depletes the dNTP pool primarily of dCTP and dATP. And this further facilitates clofarabine triphosphate incorporated into the DNA^[1]. Though inhibition of DNA synthesis is mainly contributed to the anti-tumor effect, the cytotoxicity of clofarabine can be implemented through induction of DNA damage and mitochondrial damage on CLL cells, thus triggering the apoptosis^[2].
• 作用机制Clofarabine can inhibit DNA synthesis and DNA strands extension through both inhibition of ribonucleotide reductase and DNA polymeraseα.

• 动物研究
  剂量	Mice[3] (i.p.): min = 20 mg/kg, max = 600 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[3] Dose 20 mg/kg Administration i.p. CL/F 2.707 L/h/kg K21 1.886 (1/h) V1/F 28.37 L/kg AUC0→t 6.124 mg/L/h K12 0.255 (1/h) T1/2α 0.356 h K10 0.095 (1/h) T1/2β 2.395 h