PT2385

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.

Product information

CAS Number: 1672665-49-4

Molecular Weight: 383.34

Formula: C17H12F3NO4S

Synonym:

PT-2385

Chemical Name: (S)-3-((2, 2-difluoro-1-hydroxy-7-(methylsulfonyl)-2, 3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile

Smiles: CS(=O)(=O)C1=CC=C(OC2=CC(F)=CC(=C2)C#N)C2CC(F)(F)[C@@H](O)C1=2

InChiKey: ONBSHRSJOPSEGS-INIZCTEOSA-N

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

Technical Data

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

In Vitro:

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.

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 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.

References:

1. Wallace EM, et al. Cancer Res. 2016, 76(18):5491-500.
2. Wehn PM, et al. J Med Chem. 2018, 61(21):9691-9721.

Products are for research use only. Not for human use.