生物活性

• 描述HIF-1α is constitutively expressed subunit of HIF-1 mediating the cellular response to hypoxia, which can be rapidly degraded by the ubiquitin-26S proteasome pathway under conditions of normoxia. PX-478 target on HIF-1α, which can selectively inhibit the hypoxia-induced increase in HIF-1a protein. Treatment with PX-478 for 16h can inhibit nuclear HIF-1αprotein level in cell lines under hypoxic (1% O2, 5%CO2, 94% N2) compared with cells under normoxia (air, 5% CO2) with IC50 values for PC-3 prostate cancer cells of 3.9 ± 2.0 μM, MCF-7 breast cancer cells of 4.0 ± 2.0 μM, HT-29 colon cancer cells of 19.4 ± 5.0 μM, Panc-1 pancreatic cancer cells of 10.1 ± 1.9 μM and BxPC-3 pancreatic cancer cells of 15.3 ± 4.8 μM, without affection on levels of HIF-1βprotein. Meanwhile, PX-478 treatment also significantly decreased the activity of a HIF-1 (measured by transiently transfected HIF-1 reporter), as well as hypoxia-induced expression of VEGF, a HIF-1-regulated protein, in MCF-7 cells in a dose-dependent manner (0 - 25 μM, for 16h) but did not affect basal levels of VEGF formation under normoxic conditions^[1]. Treatment with PX-478, i.p., at dose of 75 or 100 mg/kg/day repressed tumor growth in female SCID mice were implanted, s.c., with SHP-77 human small cell lung cancer cells. Also treatment with PX-478, i.p., at dose of 100mg/kg/day suppressed tumor growth in male SCID mice implanted s.c. with PC-3 prostate cancer cells^[2]. Up to now, phase 1 studies of PX-478 treatment for advanced solid tumors and lymphoma have been completed (see https://www.clinicaltrials.gov/)
• 作用机制 The action of PX-478 on HIF-1αmay due to: 1. Modulation of HIF-1αubiquitination; 2. Inhibition on HIF-1α transcription; 3. Inhibition on HIF-1α translation.

• 动物研究
  剂量	Mice[2] (i.p.): 100 mg/kg, 120 mg/kg, 150 mg/kg
  给药途径	i.p., i.v., p.o.
  动物药代数据	Animal Mice[2] Dose 150 mg/kg Administration i.v. i.p. p.o. Cmax 428 μg/ml (i.v.) 465 μg/ml (i.p.) 158 μg/ml (p.o.) T1/2 60.6 min (i.v.) 47.4 min (i.p.) 27.9 min (p.o.) F 91% (i.p.) 86% (p.o.) Vss 380 ml/kg (i.v.) AUC 31918 μg/ml (i.v.) 29122 μg/ml (i.p.) 27474 μg/ml (p.o.) CL 4.7 ml/min/kg (i.v.)