Chemistry and pharmacology of ceritinib


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Ceritinib (formerly known as LDK378 and marketed as Zykadia™, synthesized from the compound TAE684 by Novartis Pharmaceuticals) is a small, orally administered ALK inhibitor prescribed to patients harboring ALK+-NSCLC that has become resistant to crizotinib therapy. The synthesized molecule has a formula C28H36ClN5O3S, an International Union of Pure and Applied Chemistry (IUPAC) name 5-chloro-2-N-(5-methyl-4-piperidin-4-yl-2-propan-2-yloxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine, and a molecular weight 557.22 g/mol (Figure 1).31Molecular ceritinib has the capacity to accept seven hydrogen bonds and can donate three hydrogen atoms for hydrogen bonding, while also maintaining nine rotatable bonds in physiological conditions. Ceritinib acts as a powerful inhibitor of ALK, yet does not demonstrate c-MET inhibition as does its predecessor crizotinib.8

Molecular docking simulations of the reported crystal structure of ceritinib have revealed the mechanism by which the molecule interacts with the kinase domain of ALK. Acting as a ligand, ceritinib binds via hydrogen bonds with amino acids of the kinase’s hinge area through both the amino nitrogen atoms and the central pyrimidine ring of the inhibitor. The ligand-active site interaction is further stabilized by a salt bridge formed between the terminal piperidine of the inhibitor with Glu1210 of the kinase domain.31 While molecular ceritinib contains almost double the amount of rotatable bonds compared to crizotinib (ceritinib maintains nine, crizotinib maintains five), the former exhibits potency toward ALK 20-fold higher than the latter.32

Ceritinib has exhibited cellular specificity to tumors harboring the ALK translocated gene through assays determining 50% of maximal inhibition of tumor cell proliferation (GI50 assays) in multiple tumor samples expressing various oncogenic drivers. Ceritinib demonstrated potency in two ALK+-NSCLC cell lines (H3112 and H2228), but failed to show significant GI50s in tumor cells expressing the other oncogenic drivers EGFR, HER2, KRAS, or PI3K.32 These findings highlight the specificity of ceritinib in targeting ALK+-NSCLC cells.

Ceritinib specifically binds to the intracellular kinase domain of the EML4–ALK fusion protein, inhibiting its phosphorylation and subsequent activation of its downstream pathways.32 This mechanism of kinase inhibition involves competitive binding in the fusion kinase domain, preventing induced structural changes that result in activated downstream pathways involved in cell growth and proliferation.32 By selectively inhibiting this oncogenic process at the initial step of irregular ALK activation, ceritinib exhibits significant antitumor activity in NSCLC patients harboring ALKtranslocations. Figure 2 represents a schematic diagram of ceritinib inhibiting phosphorylation of the EML4–ALK kinase and deactivating downstream growth pathways.

Ceritinib maintains a remarkable pharmacokinetic profile in mammals with only mild to few severe side effects in human patients. The maximum tolerated dose (MTD) of ceritinib is 750 mg on an empty stomach, with antitumor results observable in patients treated with 400 mg daily. The maximum human plasma concentration of ceritinib is realized 4–6 hours after receiving the MTD.33