Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models.

Abstract

Phosphoinositide 3-kinase (PI3K) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. Wortmannin and its analogues are potent PI3K inhibitors whose therapeutic use has been impeded by inherent defects such as instability and toxicity. Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development.

• Authors: Tianmin Zhu, Jianxin Gu, Ker Yu, Judy Lucas, Ping Cai, Russ Tsao, Yumin Gong, Fangbiao Li, Inder Chaudhary, Parimal Desai, Mark Ruppen, Mahdi Fawzi, James Gibbons, Semiramis Ayral-Kaloustian, Jerauld Skotnicki, Tarek Mansour, Arie Zask
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 4 Pg. 1373-8 (Feb 23 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16480272 (Publication Type: Journal Article)

Chemical References

• Androstadienes
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• pegylated 17-hydroxywortmannin
• 17-hydroxywortmannin
• Polyethylene Glycols
• Wortmannin

Topics

• Androstadienes (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Humans
• Mice
• Mice, Nude
• Phosphoinositide-3 Kinase Inhibitors
• Polyethylene Glycols (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Wortmannin
• Xenograft Model Antitumor Assays