Pegylated Wortmannin and 17-Hydroxywortmannin Conjugates as Phosphoinositide 3-Kinase Inhibitors Active in Human Tumor Xenograft Models

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-02, Vol.49 (4), p.1373-1378
Main Authors: Zhu, Tianmin, Gu, Jianxin, Yu, Ker, Lucas, Judy, Cai, Ping, Tsao, Russ, Gong, Yumin, Li, Fangbiao, Chaudhary, Inder, Desai, Parimal, Ruppen, Mark, Fawzi, Mahdi, Gibbons, James, Ayral-Kaloustian, Semiramis, Skotnicki, Jerauld, Mansour, Tarek, Zask, Arie
Format: Article
Language:English
Subjects:
Androstadienes - chemical synthesis
Androstadienes - chemistry
Androstadienes - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
General aspects
Humans
Medical sciences
Mice
Mice, Nude
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Polyethylene Glycols - chemical synthesis
Polyethylene Glycols - chemistry
Polyethylene Glycols - pharmacology
Structure-Activity Relationship
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050901o