Anaplastic lymphoma kinase (ALK) is a cell membrane receptor tyrosine kinase associated with chromosomal translocations resulting in the identification of oncogenic proteins that drive a subset of specific cancers.  Deregulated ALK acts through over expression in human glioblastoma or chromosome translocation in both anaplastic large cell lymphoma (NPM-ALK) and non-small cell lung cancer (EML4-ALK).  Interest in ALK has increased significantly with the recent FDA approval of crizotinib for the treatment of locally advanced or metastatic NSCLC that is ALK positive.  Here we present the results of our efforts to synthesize macrocycles designed to rigidly lock an energy-minimized bioactive conformation of our diaminopyrimidine scaffold.

Conformationally constrained diaminopyrimidines: Identification of potent ALK inhibitors

248th National Meeting (2014)

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