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

• DOI: 10.1021/jm400402q
• Publication Date: 2013-06-07T11:08:41Z
• Authors: Thomas 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. Pfer...; 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 Miche...
• Keywords: Male; 0301 basic medicine; Clinical Trials, Phase I as Topic; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays; Rats; 3. Good health; Macaca fascicularis; Structure-Activity Relationship; 03 medical and health sciences; Clinical Trials, Phase II as Topic; Dogs; Pyrimidines; Neoplasms; Animals; Humans; Anaplastic Lymphoma Kinase; Sulfones; Protein Kinase Inhibitors

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.