A Type-II Kinase Inhibitor Capable of Inhibiting the T315I "Gatekeeper" Mutant of Bcr-Abl

被引：64

作者：

Choi, Hwan Geun ^{[1
,2
,5
]}

Ren, Pingda ^{[3
]}

Adrian, Francisco ^{[3
]}

Sun, Fangxian ^{[3
]}

Lee, Hyun Soo ^{[3
]}

Wang, Xia ^{[3
]}

Ding, Qiang ^{[3
]}

Zhang, Guobao ^{[3
]}

Xie, Yongping ^{[3
]}

Zhang, Jianming ^{[1
,2
]}

Liu, Yi ^{[3
]}

Tuntland, Tove ^{[3
]}

Warmuth, Markus ^{[3
]}

Manley, Paul W. ^{[4
]}

Mestan, Juergen ^{[4
]}

Gray, Nathanael S. ^{[1
,2
]}

Sim, Taebo ^{[3
,5
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Novartis Res Fdn, Dept Chem, Genom Inst, San Diego, CA 92121 USA

[4] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland

[5] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 136791, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

关键词：

TYROSINE KINASE; AURORA KINASES; IN-VITRO; C-SRC; IMATINIB; POTENT; RESISTANCE; TARGET; GROWTH; SENSITIVITY;

D O I：

10.1021/jm901808w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M35I T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.

引用

页码：5439 / 5448

页数：10

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