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.
Zhu
Tianmin
T
Preclinical Development, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
Gu
Jianxin
J
Yu
Ker
K
Lucas
Judy
J
Cai
Ping
P
Tsao
Russ
R
Gong
Yumin
Y
Li
Fangbiao
F
Chaudhary
Inder
I
Desai
Parimal
P
Ruppen
Mark
M
Fawzi
Mahdi
M
Gibbons
James
J
Ayral-Kaloustian
Semiramis
S
Skotnicki
Jerauld
J
Mansour
Tarek
T
Zask
Arie
A
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