Since the launch of Gleevec in 2001, protein kinases have emerged as attractive therapeutic targets for the treatment of various cancers. One of these, anaplastic lymphoma kinase (ALK), has attracted a great deal of attraction due to its oncogenic potential and essential role in the pathogenesis of a wide variety of human cancers, such as ALCLs, NSCLC, breast cancer, colorectal cancer, neuroblastoma, ovarian cancer, etc. Currently, seven ALK inhibitors have been approved under clinical investigation and two inhibitors, crizotinib and ceritinib, were approved by FDA for the treatment of locally advanced and ALK-positive metastatic NSCLC patients who were previously treated with-, or intolerant to crizotinib respectively. Therefore, the development of ALK inhibitors targeting the ATP binding site could be a tremendous interest for the treatment of ALK-driven cancers. In this study, we screened in-house library of 350 furanopyrimidines for vitro enzyme-based testing of ALK inhibition at 10 mM and BPR4K0050S0 bearing a unique (4-hydroxyphenethyl)amino substituent possessed 62% inhibition. The further structural modification with the objectives of improving the potency based on structure biology and docking studies. A promising compound, BPR4K0059S0 with 2,4-diaminopyrimidine scaffold, exhibited inhibitory activity against ALKWT and ALKL1196M with IC50 values of 142 nM and 193 nM respectively, and showed anti-proliferation activity against KARPAS-299 cell line with an IC50 value of 328 nM.

Discovery of 2,4-diaminopyrimidines bearing a unique pharmacophore as anaplastic lymphoma kinase inhibitors

250th National Meeting (2015)

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