Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer

被引：220

作者：

Burger, Matthew T. ^{[1
]}

Pecchi, Sabina ^{[1
]}

Wagman, Allan ^{[1
]}

Ni, Zhi-Jie ^{[1
]}

Knapp, Mark ^{[1
]}

Hendrickson, Thomas ^{[1
]}

Atallah, Gordana ^{[1
]}

Pfister, Keith ^{[1
]}

Zhang, Yanchen ^{[1
]}

Bartulis, Sarah ^{[1
]}

Frazier, Kelly ^{[1
]}

Ng, Simon ^{[1
]}

Smith, Aaron ^{[1
]}

Verhagen, Joelle ^{[1
]}

Haznedar, Joshua ^{[1
]}

Huh, Kay ^{[1
]}

Iwanowicz, Ed ^{[1
]}

Xin, Xiaohua ^{[1
]}

Menezes, Daniel ^{[1
]}

Merritt, Hanne ^{[1
]}

Lee, Isabelle ^{[1
]}

Wiesmann, Marion ^{[1
]}

Kaufman, Susan ^{[1
]}

Crawford, Kenneth ^{[1
]}

Chin, Michael ^{[1
]}

Bussiere, Dirksen ^{[1
]}

Shoemaker, Kevin ^{[1
]}

Zaror, Isabel ^{[1
]}

Maira, Sauveur-Michel ^{[1
]}

Voliva, Charles F. ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Emeryville, CA 94608 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 10期

关键词：

NVP-BKM120; phosphoinositide-3-kinase; PI3K/AKT3; pathway; TARGET; RAPAMYCIN; 3-KINASES; PATHWAY;

D O I：

10.1021/ml200156t

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocydic pyrirnidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrirnidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.

引用

页码：774 / 779

页数：6

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