生物活性

• 靶点	Pol I-driven rRNA transcription IC50:142nM

• 描述Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells, selectively inhibits Pol I with IC₅₀ value of 142 nM in the HCT-116 cells. The IC₅₀ for rRNA synthesis for the BJ-hTert normal cell line of 74 nM correlated well with the IC₅₀ values of the solid tumor cell lines (IC₅₀ = 142, 113, and 54 nM, respectively) illustrating that CX-5461 can equivalently inhibit Pol I transcription in cancer and normal cells, but the normal cells can tolerate reductions in rRNA synthesis without induction of cell death. Treatment with 300 nM CX-5461 for 24 hours caused a significant increase from 15% ± 3% to 67% ± 2% in LC3B-II staining (P = 0.0041) in A375 and from 19% ± 2% to 62% ± 3% in LC3B-II staining (P = 0.002) in MIA PaCa-2 cells (LC3B-II, a known marker of autophagy). In addition to autophagy, CX-5461 (300 nM; 24 hours) was able to induce senescence in both cell lines. In two murine xenograft models of human cancers, MIA PaCa-2 and A375, CX-5461 was administered orally (50 mg/kg) either once daily or every 3 days. CX-5461 demonstrated significant MIA PaCa-2 TGI (tumor growth inhibition) equal to 69% on day 31. Likewise, CX-5461 demonstrated significant A375 TGI equal to 79% on day 32.

• 动物研究
  剂量	Mice: 30 mg/kg[4] (i.v.)， 125 mg/kg[1] (i.p.), 50 mg/kg[1] (p.o.)
  给药途径	i.v., i.p., p.o.
  动物药代数据	Animal Mice[3] Rats[3] Dogs[3] Monkeys[3] Dose 25 mg/kg 25 mg/kg 25 mg/kg 25 mg/kg Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. F 24% (p.o.) 29% (p.o.) 38% (p.o.) 45% (p.o.) Vd 0.24 L/kg (i.v.) 0.08 L/kg (i.v.) 21 L/kg (i.v.) 33 L/kg (i.v.) T1/2 6.3 h (i.v.) 5.9 h (i.v.) 8.9 h (i.v.) 12.8 h (i.v.) CLs 0.03 L/h/kg (i.v.) 0.06 L/h/kg (i.v.) 1.6 L/h/kg (i.v.) 1.8 L/h/kg (i.v.) AUC0→24h 93373 ng·h/ml (p.o.) 92057 ng·h/ml (p.o.) 3890 ng·h/mL (p.o.) 2597 ng·h/mL (p.o.)