生物活性

• 描述PT2385 is a specific HIF-2α inhibitor with Kd value less than 50nM, with selectivity to HIF-2α over HIF-1α. Binding of PT-2385 to HIF-2α could block the heterodimerization of HIF-2α with ARNT. Oral administration of PT-2385 at 3mg/kg or 10mg/kg, b.i.d., could suppress the tumor growth in 786-O subcutaneous xenograft model of ccRCC (VHL^-/-, HIF-1α^-/-, HIF-2α^+/+), with inhibition of tumor-derived hVEGFA (but not mouse VEGFA) protein level, proliferation and angiogenesis observed. The inhibition of HIF-2α-regulated gene Cyclin D1, VEGFA, PAI-1 and GLUT1, on mRNA levels could be observed after PT-2385 treatment. Also PT-2385 exhibited in vivo tumor growth suppression in a Sunitinib-resistant PDX subcutaneous xenograft model of ccRCC (VHL^-/-, HIF-1α^+/+, HIF-2α^+/+) at dose of 30mg/kg. PT-2385 at concentration of 20μM could suppress HIF-2α level and partly reverse the decrease of AR and the increase of downstream signals, including pSTAT3, pAKT and pERK, by sorafenib treatment in HepG2 and SKhep1 cells. Also it significantly enhanced sorafenib to suppress HCC invasion in HepG2, SKhep1 and Huh7 cells. And this enhance by PT-2385 could also be observed in vivo. Inhibition HIF-2α by PT2385 had preventive and therapeutic effects on metabolic disorders dependent on intestine HIF-2α, which could markedly reduce intestine and serum ceramide levels, as well as improve steatosis.

• 动物研究
  剂量	Rat: 30 mg/kg, 100 mg/kg[2] (p.o., BID) Mice: 5 mg/kg[3] (p.o., BID), 10 mg/kg[4] (p.o., BID), 50 mg/kg[5] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[6] Dogs[6] Dose 3 mg/kg (i.v.) 10 mg/kg (p.o.) 3 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 40% (p.o.) 87% (p.o.) T1/2 3.3 h (p.o.) 11.0 h (p.o.) CL 34.6 ml/min/kg (i.v.) 21.5 ml/min/kg (i.v.) Vss 6.24 L/kg (i.v.) 8.6 L/kg (i.v.) AUC0→t 5.12 h·μM (p.o.) 6.2 h·μM (p.o.)