PT2385

• CAS: 1672665-49-4
• Catalog Number: ACM1672665494
• Category: Inhibitors
• Molecular Weight: 383.34
• Molecular Formula: C17H12F3NO4S
• Description: PT2385 is an orally active, small molecule inhibitor of hypoxia inducible factor (HIF)-2alpha, with potential antineoplastic activity. Upon oral administration, HIF-2alpha inhibitor PT2385 allosterically binds to HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate tumor cell growth and survival.
• Synonyms: PT2385; PT-2385; PT 2385
• IUPAC Name: (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
• Canonical SMILES: CS(C(C=C1)=C2C(CC(F)(F)[C@H]2O)=C1OC3=CC(C#N)=CC(F)=C3)(=O)=O
• InChI: InChI=1S/C17H12F3NO4S/c1-26(23,24)14-3-2-13(12-7-17(19,20)16(22)15(12)14)25-11-5-9(8-21)4-10(18)6-11/h2-6,16,22H,7H2,1H3/t16-/m0/s1
• InChI Key: ONBSHRSJOPSEGS-INIZCTEOSA-N
• Solubility: Soluble in DMSO, not in water
• Appearance: Solid powder
• Shelf Life: >2 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• Biological Target: PT-2385 is a selective HIF-2α inhibitor with a Ki of less than 50 nM.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 53.27; H, 3.16; F, 14.87; N, 3.65; O, 16.69; S, 8.36
• Exact Mass: 383.0439
• HS Tariff Code: 2934.99.9001
• In Vitro Activity: PT2385 inhibition of HIF2α transcriptional activity in cells was evaluated by qPCR quantitation of known HIF2α target gene transcripts. Treatment of 786-O cells with PT2385 significantly reduces the levels of mRNA for CCND1, VEGF-A, GLUT1, and PAI-1 in a concentration-dependent manner (Fig. 3A). The specificity of PT2385 was further evaluated in Hep3B hepatoma cells, which accumulate both HIF1α and HIF2α proteins under hypoxia and where HIFα-specific gene regulation has been previously delineated. Treatment of Hep3B cells with PT2385 reduces hypoxia-induced expression of erythropoietin (EPO) and PAI-1, both known HIF2α target genes (26-28). Compound treatment has no effect on expression of either PGK1 or pyruvate dehydrogenase kinase 1 (PDK1) genes, which are specifically regulated by HIF1α in Hep3B cells (Fig. 3B; refs. 29, 30). Consistent with the gene expression data, PT2385 only disrupts HIF2α, but not HIF1α, heterodimerization with ARNT in Hep3B cells (Fig. 3C). PT2385 has no effect on the proliferation or viability of 786-O and A498 cells in culture at concentration as high as 10 μmol/L (Supplementary Fig. S1). This result is consistent with the observations that shRNA- or siRNA-mediated HIF2α knockdown does not affect cell proliferation in vitro. Collectively, the in vitro data indicate that PT2385 is a potent and highly selective inhibitor of HIF2α-dependent gene expression.; Reference: Cancer Res. 2016 Sep 15;76(18):5491-500. http://cancerres.aacrjournals.org/lookup/pmidlookup?view=long&pmid=27635045
• In Vivo Activity: Tumor xenografts were established in the flanks of SCID/beige mice with the 786-O and A498 RCC cell lines. When tumor size reached 200 to 300 mm3, the mice were administered PT2385 by oral gavage at indicated doses on a daily basis. In the 786-O xenograft model, both 3 and 10 mg/kg PT2385 given twice daily result in a rapid, dose-dependent tumor regression. In contrast, a multi-tyrosine kinase inhibitor, sunitnib, at 40 mg/kg given once daily produces only tumor stasis (Fig. 5A and B). In the A498 xenograft model, PT2385 induces tumor stasis at 6 mg/kg once daily and tumor regression at 20 and 60 mg/kg once daily. Sunitinib at 40 mg/kg once daily has a similar effect as the higher doses of PT2385 (Fig. 5C and D). The antitumor efficacy of PT2385 was further evaluated in a patient-derived xenograft (PDX) model. The ccRCC tumor is VHL deficient, expresses both HIF1α and HIF2α (Supplementary Fig. S5), and is derived from a patient that progressed after treatment with sunitinib and everolimus. Tumor-bearing mice were treated with 30 mg/kg of PT2385 twice daily or 40 mg/kg of sunitinib once daily. After 4 weeks, PT2385 treatment completely inhibited tumor growth, whereas sunitinib had no impact (Fig. 5E). These data indicate that PT2385 has efficacy in VHL-mutant ccRCC tumors that express both HIF1α and HIF2α proteins. Furthermore, PT2385 demonstrated superior efficacy to sunitinib in 2 of 3 models evaluated, supporting that HIF2α antagonism has broad antitumor effects beyond antiangiogenesis in ccRCC. PT2385 was well tolerated in all three models, with no weight loss or behavioral changes observed (Supplementary Fig. S6A-S6C).; Reference: Cancer Res. 2016 Sep 15;76(18):5491-500. http://cancerres.aacrjournals.org/lookup/pmidlookup?view=long&pmid=27635045
• Shipping: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).