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.
CAS Number: 1672665-49-4
Molecular Weight: 383.34
Chemical Name: (S)-3-((2, 2-difluoro-1-hydroxy-7-(methylsulfonyl)-2, 3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: DMSO : ≥ 50 mg/mL (130.43 mM)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined
HS Tariff Code: 382200
How to use
PT2385 blocks HIF-2α dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibits the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. 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. 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. Treatment of Hep3B cells with PT2385 reduces hypoxia-induced expression of erythropoietin (EPO) and PAI-1, both known HIF2α target genes.
PT2385 exhibits good mouse oral bioavailability (110%) and low to medium in vivo clearance. In mice administrated via intravenous injection, the t1/2 of PT2385 is 3.3 h. In rat pharmacokinetics studies, the oral bioavailability (F) when dosed at 10 mg/kg is 40% and the t1/2 is 3.3 h. In dogs, the oral bioavailability (F) is 87% and the t1/2 is 11 h. Treatment of tumor-bearing mice with PT2385 causes dramatic tumor regressions (clear cell renal cell carcinomas). PT2385 exhibits no adverse effect on cardiovascular performance.
- Wallace EM, et al. Cancer Res. 2016, 76(18):5491-500.
- Wehn PM, et al. J Med Chem. 2018, 61(21):9691-9721.
Products are for research use only. Not for human use.
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