PX-478 --- Hypoxia-inducible Factor-1α (HIF-1α) Inhibitor

PX-478 is HIF-1alpha inhibitor, is also an orally active small molecule with potential antineoplastic activity. Although its mechanism of action has yet to be fully elucidated, HIF1-alpha inhibitor PX-478 appears to inhibit hypoxia-inducible factor 1-alpha (HIF1A) expression, which may result in decreased expression of HIF1A downstream target genes important to tumor growth and survival, a reduction in tumor cell proliferation, and the induction of tumor cell apoptosis. The inhibitory effect of this agent is independent of the tumor suppressor genes VHL and p53 and may be related to derangements in glucose uptake and metabolism due to inhibition of glucose transporter-1 (Glut-1). PX-478 has excellent activity against established human tumor xenografts, providing tumor regressions with prolonged growth delays which correlate positively with HIF-1 levels. PX-478 is a highly water soluble molecule, with good i.v., i.p. and p.o. antitumor activity. It is rapidly absorbed following oral and i.p. administration and gives excellent Cmax and AUC via these routes.

Product information

CAS Number: 685898-44-6

Molecular Weight: 394.12

Formula: C13H20Cl4N2O3

Chemical Name: 4-[bis(2-chloroethyl)oxidoamino]-L-phenylalanine hydrochloride

Smiles: Cl.Cl.N[C@@H](CC1C=CC(=CC=1)[N+]([O-])(CCCl)CCCl)C(O)=O

InChiKey: GIGCDIVNDFQKRA-LTCKWSDVSA-N

InChi: InChI=1S/C13H18Cl2N2O3.2ClH/c14-5-7-17(20,8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19;;/h1-4,12H,5-9,16H2,(H,18,19);2*1H/t12-;;/m0../s1

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 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:

PX-478 was used at 1-10 µM final concentration in various in vitro assays. It is found to be not stable at basic buffer, and stable in acidic buffer.

In Vivo:

PX-478 was dosed to mice bearing tumor via IP injection or oral gavage at 100-120 mg/kg once per day. Formulation is 0.9% NaCl. Xenografts models are MCF-7 human breast cancer, HT-29 colon cancer, PC-3 prostate cancer, DU-145 prostate cancer, OvCar-3 ovarian cancer, A-549 non-small cell lung cancer, SHP-77 small cell lung cancer, and Caki-1 renal cancer, Panc-1, MiaPaCa, or BxPC-3 pancreatic cancer.

References:

1. Welsh S, et al. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. (2004) Mol Cancer Ther. 3(3):233-44.
2. Koh MY, et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. (2008) Mol Cancer Ther. 7(1):90-100.
3. Sun K, et al. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction. (2013) Mol Cell Biol. 33(5):904-17.

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

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