Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors

Bioorg Med Chem Lett. 2016 Feb 1;26(3):1090-1096. doi: 10.1016/j.bmcl.2015.11.049.

Pierre-Yves Michellys ¹, Bei Chen ¹, Tao Jiang ¹, Yunho Jin ¹, Wenshuo Lu ¹, Thomas H Marsilje ¹, Wei Pei ¹, Tetsuo Uno ¹, Xuefeng Zhu ¹, Baogen Wu ¹, Truc Ngoc Nguyen ¹, Badry Bursulaya ¹, Christian Lee ¹, Nanxin Li ¹, Sungjoon Kim ¹, Tove Tuntland ¹, Bo Liu ¹, Frank Sun ², Auzon Steffy ¹, Tami Hood ³

Affiliations

1 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
2 Sanofi Oncology, 640 Memorial Drive, Cambridge, MA 02139, United States.
3 Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, United States.

PMID: 26750252 DOI: 10.1016/j.bmcl.2015.11.049

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.

Keywords

ALK; Hinge; Karpas299; Scaffold morphing.

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