Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase in the insulin receptor superfamily. ALK has been recognized as an attractive therapeutic target since 2007, when a novel oncogenic fusion gene of ALK with the echinoderm microtubule-associated protein-like 4 (EML4) was identified in non-small cell lung cancer (NSCLC). Alectinib is a highly selective CNS-active ALK inhibitor created by Chugai Pharmaceutical, a member of the Roche Group. Alectinib has twice been granted Breakthrough Therapy Designation by the FDA; once in June 2013 for patients with ALK-positive NSCLC who have progressed on crizotinib, and again in September 2016 for adult patients with ALK-positive advanced NSCLC who have not received prior treatment with an ALK inhibitor. To develop alectinib, we first identified a hit compound, CH5273125, with an IC50 value of 1336 nM from our company library of kinase inhibitors. CH5273125 has a unique tetracyclic benzofuran scaffold in comparison with other reported ALK inhibitors. We carried out chemical modification focusing on the potency of its anti-tumor activity and the kinase selectivity to identify the clinical compound, alectinib (CH542802). Alectinib, a selective and potent ATP-competitive ALK inhibitor, inhibits cellular growth of ALK-addicted tumor cell lines and shows potent in vivo efficacy in an EML4-ALK-positive H2228 xenograft model. It also has superior DMPK and safety profiles in rodent and non-rodent. Based on the results of a phase I/II clinical trial that started in 2010 in Japan, alectinib was approved for the treatment of ALK fusion gene-positive unresectable, recurrent/advanced NSCLC by the Japanese Ministry of Health, Labour and Welfare (MHLW) in July 2014. Alectinib is also being developed by F. Hoffmann-La Roche AG in other countries, including the EU and US (cord: RG7853). In December 2015, the FDA granted accelerated approval to alectinib for the treatment of people with ALK-positive metastatic NSCLC who have progressed on, or are intolerant to, crizotinib.

Discovery and development of alectinib, a selective and potent ALK inhibitor for treatment of ALK-positive advanced non-small cell lung cancer

255th National Meeting (2018)

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