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.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02293980	ccRCC RCC ... more >> Kidney Cancer Clear Cell Renal Cell Carcinoma Renal Cell Carcinoma Collapse <<	Phase 1	Active, not recruiting	August 2020	-
  NCT03216499	Recurrent Glioblastoma	Phase 2	Active, not recruiting	August 31, 2019	United States, Alabama ... more >> UAB Comprehensive Cancer Center Birmingham, Alabama, United States, 35294-3410 United States, California Jonsson Comprehensive Cancer Center at UCLA Los Angeles, California, United States, 90095 UCSF Comprehensive Cancer Center San Francisco, California, United States, 94115 United States, Maryland Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, United States, 21231 United States, Massachusetts Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, Michigan Henry Ford Hospital Detroit, Michigan, United States, 48202 United States, New York Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10021 United States, North Carolina Wake Forest University Comprehensive Cancer Center Winston-Salem, North Carolina, United States, 27157 United States, Ohio Cleveland Clinic Taussig Cancer Center Cleveland, Ohio, United States, 44195 United States, Pennsylvania Abrams Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania, United States, 19104 Hillman Cancer Center at University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania, United States, 15232 Collapse <<
  NCT03108066	VHL Gene Mutation ... more >> VHL VHL Syndrome VHL Gene Inactivation Von Hippel Von Hippel-Lindau Disease Von Hippel's Disease Von Hippel-Lindau Syndrome, Modifiers of Clear Cell Renal Cell Carcinoma Clear Cell RCC ccRCC Collapse <<	Phase 2	Active, not recruiting	September 2022	United States, Maryland ... more >> National Institutes of Health Clinical Center Bethesda, Maryland, United States, 20892 Collapse <<

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• 参考文献

• [1] Chen W, Hill H, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016 Nov 3;539(7627):112-117.

  [2] Wallace EM, Rizzi JP, et al. A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma. Cancer Res. 2016 Sep 15;76(18):5491-500.

  [3] Liu N, Luo J, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J Clin Invest. 2019 Feb 1;129(2):631-646.

  [4] Xu R, Wang K, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma. J Med Chem. 2019 Aug 8;62(15):6876-6893.

  [5] Xie C, Gao X, et al. Metabolic Profiling of the Novel Hypoxia-Inducible Factor 2α Inhibitor PT2385 In Vivo and In Vitro. Drug Metab Dispos. 2018 Apr;46(4):336-345.

  [6] Wehn PM, Rizzi JP, et al. Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate ( S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385). J Med Chem. 2018 Nov 8;61(21):9691-9721.

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