Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase (RTK), originally identified in 1994 in anaplastic large-cell lymphoma (ALCL) as a translocated form by fusing its intracellular domain to the N-terminal portion of nucleophorsmin (NPM), however, its normal function has not been fully understood. In 2007, the ALK fusion gene - EML4-ALK was identified specifically existing in lung cancer and recognized a distinct molecular subset of NSCLC populations. Since then, ALK has rapidly emerged as a novel and promising 'personalized' anticancer drug target. Crizotinib, one of the small molecule ALK inhibitors has been successfully launched in 2011; however, similar to other RTK inhibitors, resistance to crizotinib has been reported within a year of starting therapy. Studies disclosed that the resistance to crizotinib was much complex with more than twenty secondary mutations, not only including the gate-keeper L1196M, and the C1156Y near the a-C-helix. In the course of our drug discovery program toward the discovery of novel RTK inhibitors, we took advantage of the 2,4-diarylaminopyrimidine (DAAP) scaffold that has long been recognized as a classical kinase inhibitor motif by introducing an amino acid side chain to the solvent interaction region to bring in additional H-bondings. Therefore, a series of new DAAP analogues (DAAPalogues) were developed (Figure 1) and one compound was identified with high potency against both wild type ALK and L1196M mutations with IC50values of 14.5 nM and 15.3 nM, respectively. Further investigations both in vitro and in vivo were also conducted. The high potency of this novel compound allows it for further evaluation.

Structural modification on the 2,4-diarylaminopyrimidine scaffold and discovery of potent inhibitors targeting both wild and mutant ALK kinases

248th National Meeting (2014)

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