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
posted on 2013-07-25, 00:00authored byThomas H. Marsilje, Wei Pei, Bei Chen, Wenshuo Lu, Tetsuo Uno, Yunho Jin, Tao Jiang, Sungjoon Kim, Nanxin Li, Markus Warmuth, Yelena Sarkisova, Frank Sun, Auzon Steffy, AnneMarie C. Pferdekamper, Allen G. Li, Sean B. Joseph, Young Kim, Bo Liu, Tove Tuntland, Xiaoming Cui, Nathanael S. Gray, Ruo Steensma, Yongqin Wan, Jiqing Jiang, Greg Chopiuk, Jie Li, W. Perry Gordon, Wendy Richmond, Kevin Johnson, Jonathan Chang, Todd Groessl, You-Qun He, Andrew Phimister, Alex Aycinena, Christian C. Lee, Badry Bursulaya, Donald S. Karanewsky, H. Martin Seidel, Jennifer L. Harris, Pierre-Yves Michellys
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.