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 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.
Preclinical Development, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
Tianmin
T
Zhu
Jianxin
J
Gu
Ker
K
Yu
Judy
J
Lucas
Ping
P
Cai
Russ
R
Tsao
Yumin
Y
Gong
Fangbiao
F
Li
Inder
I
Chaudhary
Parimal
P
Desai
Mark
M
Ruppen
Mahdi
M
Fawzi
James
J
Gibbons
Semiramis
S
Ayral-Kaloustian
Jerauld
J
Skotnicki
Tarek
T
Mansour
Arie
A
Zask
D000730:Androstadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
D000730:Androstadienes; D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; C509268:pegylated 17-hydroxywortmannin; C053480:17-hydroxywortmannin; D011092:Polyethylene Glycols; D000077191:Wortmannin