Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

被引：346

作者：

Marsilje, Thomas H. ^{[1
]}

Pei, Wei ^{[1
]}

Chen, Bei ^{[1
]}

Lu, Wenshuo ^{[1
]}

Uno, Tetsuo ^{[1
]}

Jin, Yunho ^{[1
]}

Jiang, Tao ^{[1
]}

Kim, Sungjoon ^{[1
]}

Li, Nanxin ^{[1
]}

Warmuth, Markus ^{[1
]}

Sarkisova, Yelena ^{[1
]}

Sun, Frank ^{[1
]}

Steffy, Auzon ^{[1
]}

Pferdekamper, AnneMarie C. ^{[1
]}

Li, Allen G. ^{[1
]}

Joseph, Sean B. ^{[1
]}

Kim, Young ^{[1
]}

Liu, Bo ^{[1
]}

Tuntland, Tove ^{[1
]}

Cui, Xiaoming ^{[1
]}

Gray, Nathanael S. ^{[1
]}

Steensma, Ruo ^{[1
]}

Wan, Yongqin ^{[1
]}

Jiang, Jiqing ^{[1
]}

Chopiuk, Greg ^{[1
]}

Li, Jie ^{[1
]}

Gordon, W. Perry ^{[1
]}

Richmond, Wendy ^{[1
]}

Johnson, Kevin ^{[1
]}

Chang, Jonathan ^{[1
]}

Groessl, Todd ^{[1
]}

He, You-Qun ^{[1
]}

Phimister, Andrew ^{[1
]}

Aycinena, Alex ^{[1
]}

Lee, Christian C. ^{[1
]}

Bursulaya, Badry ^{[1
]}

Karanewsky, Donald S. ^{[1
]}

Seidel, H. Martin ^{[1
]}

Harris, Jennifer L. ^{[1
]}

Michellys, Pierre-Yves ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 14期

关键词：

RECEPTOR TYROSINE KINASE; NON-HODGKINS-LYMPHOMA; CELL LUNG-CANCER; EXPERIMENTAL-MODELS; ANTITUMOR-ACTIVITY; DRUG DISCOVERY; SOLID TUMORS; C-MET; GENE; IDENTIFICATION;

D O I：

10.1021/jm400402q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

引用

页码：5675 / 5690

页数：16

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