Home Epigenetics HIF inhibitor PT2385

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PT2385 HIF-2α Inhibitor

Cat.No.S8352

PT2385 is a HIF-2α antagonist with luciferase EC50 of 27 nM and no significant off-target activity.
PT2385 HIF inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 383.34

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
786-O Function assay 24 hrs Antagonist activity at HIF-2alpha in human 786-O cells co-expressing HIF responsive element after 24 hrs by ONE-Glo luciferase reporter gene assay, EC50 = 0.027 μM. 30289716
786-O Function assay 24 hrs Antagonist activity at HIF-2alpha in human 786-O cells assessed as reduction in VEGFA concentration after 24 hrs by ELISA, EC50 = 0.041 μM. 30289716
786-O Function assay 24 hrs Antagonist activity at HIF-2alpha in human 786-O cells assessed as free plasma adjusted EC50 for reduction in VEGFA concentration after 24 hrs by ELISA, EC50 = 0.158 μM. 30289716
786-O Function assay 10 mg/kg 3 days In vivo inhibition of HIF-2alpha in SCID/Biege mouse xenografted with human 786-O cells assessed as reduction in CCND1 mRNA levels at 10 mg/kg, po bid for 3 days and measured after 12 hrs post last dose by qRT-PCR analysis 30289716
786-O Function assay 10 mg/kg 3 days In vivo inhibition of HIF-2alpha in SCID/Biege mouse xenografted with human 786-O cells assessed as reduction in VEGFA mRNA levels at 10 mg/kg, po bid for 3 days and measured after 12 hrs post last dose by qRT-PCR analysis 30289716
786-O Antitumor assay 10 mg/kg 21 days Antitumor activity against human 786-O cells xenografted in SCID/Biege mouse assessed as tumor regression at 10 mg/kg, po bid for 21 days 30289716
786-O Function assay 10 mg/kg 3 days Minimum drug level in SCID/Biege mouse xenografted with human 786-O cells at 10 mg/kg, po bid for 3 days and measured after 12 hrs post last dose by LC-MS/MS analysis 30289716
786-O Function assay 10 mg/kg 3 days In vivo inhibition of HIF-2alpha in SCID/Biege mouse xenografted with human 786-O cells assessed as reduction in tumor derived VEGFA protein levels at 10 mg/kg, po bid for 3 days and measured after 12 hrs post last dose by ELISA 30289716
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Chemical Information, Storage & Stability

Molecular Weight 383.34 Formula

C17H12F3NO4S

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1672665-49-4 -- Storage of Stock Solutions

Synonyms N/A Smiles CS(=O)(=O)C1=C2C(C(CC2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)(F)F)O

Solubility

In vitro
Batch:

DMSO : 77 mg/mL (200.86 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 5 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
HIF-2α [1]
(Cell-free assay)
27 nM(EC50)
In vitro

PT2385 blocks HIF-2α dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. This compound inhibits the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. It 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 this chemical significantly reduces the levels of mRNA for CCND1, VEGF-A, GLUT1, and PAI-1 in a concentration-dependent manner. Treatment of Hep3B cells with this agent reduces hypoxia-induced expression of erythropoietin (EPO) and PAI-1, both known HIF2α target genes[2].
In vivo

PT2385 exhibits good mouse oral bioavailability (110%) and low to medium in vivo clearance. In mice administrated via intravenous injection, the t1/2 of this compound 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[1]. Treatment of tumor-bearing mice with this chemical causes dramatic tumor regressions (clear cell renal cell carcinomas). It exhibits no adverse effect on cardiovascular performance[2].
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02553356 Completed
Healthy
Peloton Therapeutics Inc. a subsidiary of Merck & Co. Inc. (Rahway New Jersey USA)
 September 2015 Phase 1

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