Description
PX-866 (502632-66-8) inhibits PI-3 Kinase with selectivity for p110α (IC50=0.1 nM). Counteracts hypoxia-related downregulation of E7 expression in HPV-positive cancer cells.2 Displays antitumor activity. Irreversible. Cell permeable.
Uses
PX-866 is an analog of wortmannin (W499400). Wortmannin is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Potent PI3K inhibitor.
Definition
ChEBI: PX-866 is an organic heterotetracyclic compound that is obtained from wortmanin via aminolysis of its furan ring by diallyl amine. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor. It is an organic heterotetracyclic compound, a delta-lactone, an acetate ester and a tertiary amino compound. It is functionally related to a wortmannin.
in vitro
in previous study, px 866 was identified to be able to inhibit purified ptdins-3-kinase and ptdins-3-kinase signaling that was measured by phospho-ser473-akt levels in ht-29 colon cancer cells [1].
Enzyme inhibitor
This orally active antifungal and antineoplastic agent (FW = 541.60 g/mol;
CAS 502632-66-8; Solubility: 40 mg/mL DMSO, water-insoluble; stable
for six months, when stored in a refrigerated desicator) is a chemically
stable wortmannin derivative that potently and irreversibly inhibits
phosphoinositide 3-kinase (IC50 = 0.1 nM) and phosphoinositide-3-kinase-
dependent signaling. PX-866 blocks PtdIns-3-kinase signaling, as
measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells (IC50 =
20 nM). PX-866 also overcomes resistance to the EGFR inhibitor gefitinib
in A-549 human non-small cell lung cancer xenografts.
in vivo
animal study found that px-866 treatment at 10 mg/kg to mice could inhibit phospho-ser473-akt in ht-29 colon tumor xenografts up to 80% with recovery taking over 48 hours after oral administration but more rapidly after iv or ip route. in addition, px-866 had in-vivo antitumor activity against s.c. ovcar-3 human ovarian cancer and a-549 human lung cancer xenografts in immunodeficient mice. moreove, px-866 could also increase the antitumor activity of cisplatin against a-549 xenografts and radiation treatment against ovcar-3 xenografts [1].
References
1) Ihle et al. (2004), Molecular pharmacology and antitumor activity of PK-866, a novel inhibitor of phosphoinositide-3-kinase signaling; Mol. Cancer Ther., 3 763
2) Bossler et al. (2019) Repression of Human Papilloma Virus Oncogene Expression Under Hypoxia is Mediated by PI3K/mTORC2/AKT Signaling; mBio,?10 e02323 [Focus Citation]
