Ceritinib

Ceritinib is an inhibitor of anaplastic lymphoma kinase (ALK; IC₅₀ = 0.2 nM).¹ It is selective for ALK over IGF-1R, InsR, STK22D, and FLT3 (IC₅₀s = 8, 7, 23, and 60 nM, respectively) as well as a panel of 25 additional kinases (IC₅₀s = >0.26 μM for all). Ceritinib inhibits the proliferation of Ba/F3 cells expressing the fusion protein nucleophosmin-ALK (NPM-ALK) or echinoderm microtubule-associated protein-like 4-ALK (ELM4-ALK; IC₅₀s = 0.02 and 0.021 μM, respectively), as well as several crizotinib-resistant NPM-ALK and ELM4-ALK mutants.² It reduces tumor growth in an H2228 non-small cell lung cancer (NSCLC) rat xenograft model when administered at a dose of 10 mg/kg per day and induces tumor regression at 25 mg/kg per day.¹ Ceritinib (25 and 50 mg/kg per day) also induces tumor regression in a Karpas299 lymphoma rat xenograft model. Formulations containing ceritinib have been used in the treatment of ALK-positive metastatic NSCLC.

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1. Marsilje, T.H., Pei, W., Chen, B., et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J. Med. Chem. 56(14), 5675-5690 (2013).

2. Fontana, D., Ceccon, M., Gambacorti-Passerini, C., et al. Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK. Cancer Med. 4(7), 953-965 (2016).