1190400-81-7Relevant articles and documents
Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors
Michellys, Pierre-Yves,Chen, Bei,Jiang, Tao,Jin, Yunho,Lu, Wenshuo,Marsilje, Thomas H.,Pei, Wei,Uno, Tetsuo,Zhu, Xuefeng,Wu, Baogen,Nguyen, Truc Ngoc,Bursulaya, Badry,Lee, Christian,Li, Nanxin,Kim, Sungjoon,Tuntland, Tove,Liu, Bo,Sun, Frank,Steffy, Auzon,Hood, Tami
, p. 1090 - 1096 (2016/05/24)
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.
