Michellys, Pierre, Chen, Bei, Jiang, Tao, Jin, Yunho, Marsilje, Thomas, Pei, Wei, Uno, Tetsuo, Wu, Baogen, Bursulaya, Badry, Lee, Christian, Li, Nanxin, Lu, Wenshuo, Zhu, Xuefeng, Nguyen, Truc, Kim, Sungjoon, Tuntland, Tove, Liu, Bo, Steffy, Auzon, Hood, Tami and Sun, Frank (2016) Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (3). pp. 1090-1096. ISSN 1464-3405

Abstract

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.

Item Type:	Article
Keywords:	ALK Hinge Karpas299 Scaffold morphing
Date Deposited:	13 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/24723