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Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors

Michellys, Pierre and Chen, Bei and Jiang, Tao and Jin, Yunho and Marsilje, Thomas and Pei, Wei and Uno, Tetsuo and Wu, Baogen and Bursulaya, Badry and Lee, Christian and Li, Nanxin and Lu, Wenshuo and Zhu, Xuefeng and Nguyen, Truc and Kim, Sungjoon and Tuntland, Tove and Liu, Bo and Steffy, Auzon and 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

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