ceritinib   Click here for help

GtoPdb Ligand ID: 7397

Synonyms: compound 15b [PMID 23742252] | LDK378 | NVP-LDK378-NX | Zykadia®
Approved drug PDB Ligand
ceritinib is an approved drug (FDA (2014), EMA (2015))
Compound class: Synthetic organic
Comment: Ceritinib is a novel, highly selective, second generation ALK inhibitor [2].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 113.62
Molecular weight 557.22
XLogP 6.55
No. Lipinski's rules broken 1
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Canonical SMILES CC(Oc1cc(C2CCNCC2)c(cc1Nc1ncc(c(n1)Nc1ccccc1S(=O)(=O)C(C)C)Cl)C)C
Isomeric SMILES CC(Oc1cc(C2CCNCC2)c(cc1Nc1ncc(c(n1)Nc1ccccc1S(=O)(=O)C(C)C)Cl)C)C
InChI InChI=1S/C28H36ClN5O3S/c1-17(2)37-25-15-21(20-10-12-30-13-11-20)19(5)14-24(25)33-28-31-16-22(29)27(34-28)32-23-8-6-7-9-26(23)38(35,36)18(3)4/h6-9,14-18,20,30H,10-13H2,1-5H3,(H2,31,32,33,34)
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Summary of Clinical Use Click here for help
Oroginally approved for the treatment of patients with non-small cell lung cancer with activating rearrangements in their ALK (anaplastic lymphoma kinase) gene (aka ALK +ve NSCLC), who have previously been treated with crizotinib and in whom drug resistance has developed [3]. In May 2017, approval was expanded to cover all patients with ALK+ve NSCLC, including previously untreated patients.
A list of clinical trials involving this drug, under its research code LDK378, is available at ClinicalTrials.gov.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily. Ceritinib inhibits the activity of ALK in cancers driven by activating ALK gene rearrangements [2-3]. The drug discovery article by Marsilje et al (2014) reviews the types of activating ALK mutations so far identified in different neoplasms. Ceritinib (compound 15b in the article) has been designed to posess superior ALK selectivity and appears to be able to overcome the problem of crizotinib resistance, which may be caused by aquired mutation in the gatekeeper residue protecting the kinase ATP binding pocket (explanation of possible mechanisms in [4] and [1]). ALK selectivity is apparent across a large panel of tested kinases, with ceritinib having an IC50 of 0.2nM for ALK [2].
Pharmacokinetics Click here for help
Cmax is achieved approximately 6 hours after dosing, with steady-state drug level achieved by approximately day 15 [3].
Terminal half-life of ceritinib is approximately 40 hours [3].
Population pharmacokinetics
Not yet dertermined.
Organ function impairment
Not yet dertermined.
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