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Novel anaplastic lymphoma kinase inhibitors targeting clinically acquired resistance.

The study by Huang et al. is an excellent example of rational structure-based and lipophilic-efficiency optimization of crizotinib (Xalkori) aimed at novel ALK inhibitors capable of overcoming clinically acquired resistance against the current drug in NSCLC patients. One of the most promising new compounds, 8e, displayed subnanomolar potency against ALK(WT) and a panel of the crizotinib-resistant mutants and demonstrated robust in vivo antitumor efficacy. The super suppressing potency of this compound on ROS1 kinase may also indicate its great potential to overcome the resistance associated with the most recently identified ROS1 mutation.