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

• Published in: Journal of medicinal chemistry Vol. 56; no. 14; pp. 5675 - 5690
• Main Authors: Marsilje, Thomas H, Pei, Wei, Chen, Bei, Lu, Wenshuo, Uno, Tetsuo, Jin, Yunho, Jiang, Tao, Kim, Sungjoon, Li, Nanxin, Warmuth, Markus, Sarkisova, Yelena, Sun, Frank, Steffy, Auzon, Pferdekamper, AnneMarie C, Li, Allen G, Joseph, Sean B, Kim, Young, Liu, Bo, Tuntland, Tove, Cui, Xiaoming, Gray, Nathanael S, Steensma, Ruo, Wan, Yongqin, Jiang, Jiqing, Chopiuk, Greg, Li, Jie, Gordon, W. Perry, Richmond, Wendy, Johnson, Kevin, Chang, Jonathan, Groessl, Todd, He, You-Qun, Phimister, Andrew, Aycinena, Alex, Lee, Christian C, Bursulaya, Badry, Karanewsky, Donald S, Seidel, H. Martin, Harris, Jennifer L, Michellys, Pierre-Yves
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.07.2013; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dogs; Humans; Life Sciences & Biomedicine; Macaca fascicularis; Male; Neoplasms - drug therapy; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Rats; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - pharmacokinetics; Sulfones - therapeutic use; Xenograft Model Antitumor Assays; CELL LUNG-CANCER; SOLID TUMORS; GENE; DRUG DISCOVERY; C-MET; NON-HODGKINS-LYMPHOMA; ANTITUMOR-ACTIVITY; IDENTIFICATION; RECEPTOR TYROSINE KINASE; EXPERIMENTAL-MODELS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400402q

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.