Anaplastic lymphoma kinase (ALK) inhibitors: A review of design and discovery

Since the launch of Gleevec in 2001, several 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 attention 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. To date, nine ALK inhibitors have entered clinical investigation for the treatment of cancers, including crizotinib, the first ALK inhibitor to be approved by the US FDA (in 2011) for the treatment of NSCLC patients. As resistance to crizotinib treatment has been reported in both preclinical and clinical settings, several second-generation ALK inhibitors to overcome both the wild-type and mutant ALK are being developed. In 2014, shortly after crizotinib was approved, the second-generation ALK inhibitor ceritinib was approved by the FDA. Biological activities of eight second-generation clinical ALK inhibitors are discussed in this review. Furthermore, the hit-to-drug evolution strategies used in the design of three ALK inhibitors-crizotinib, alectinib and ceritinib-are described in detail, to help medicinal chemists to understand and devise similar strategies to overcome lead development issues, such as potency, selectivity and metabolism, in the drug discovery projects.