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Ceritinib (LDK378)

Names

[ CAS No. ]:
1032900-25-6

[ Name ]:
Ceritinib (LDK378)

[Synonym ]:
2,4-Pyrimidinediamine, 5-chloro-N-[2-[(1-methylethyl)sulfonyl]phenyl]-N-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-
5-Chloro-N-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine
S7083
5-chloro-2-N-(5-methyl-4-piperidin-4-yl-2-propan-2-yloxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine
NVP-LDK378-NX
ZYKADIA
LDK378 Ceritinib
LDK378
LDK-378
CS-1406
QC-5183
5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
LDK 378
5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-ylphenyl)-N4-[2-(isopropylsulfonyl)phenyl]-pyrimidine-2,4-diamine
Ceritinib

Biological Activity

[Description]:

Ceritinib (LDK378) is a potent and specific ALK inhibitor with an IC50 of 0.2 nM.

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ALK
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> IGF-1R
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Insulin Receptor
Research Areas >> Cancer

[Target]

IC50: 0.2 nM (ALK), 7 nM (InsR), 8 nM (IGF-1R), 23 nM (STK22D), 60 nM (FLT3), 260 nM (FGFR2)[1]


[In Vitro]

Ceritinib (LDK378) also inhibits RET (IC50=400 nM), FGFR3 (IC50=430 nM), LCK (IC50=560 nM), JAK2 (IC50=610 nM), Aurora (IC50=660 nM), LYN (50=840 nM), EGFR (IC50=900 nM), and FGFR4 (IC50=950 nM)[1]. Ceritinib (LDK378) retains high potency against the ALK enzymatic activity with an IC50 value of 200 pM and shows only strong inhibition against IGF-1R, InsR, and STK22D out of a panel of 46 kinases with a minimum selectivity of 70-fold. In Ba/F3 cells transfected with various kinases, Ceritinib inhibits ALK activity with an IC50 value of 40.7 nM and had IC50 values of >100 nM against all other kinases tested. Ceritinib (LDK378) shows potent antiproliferative activity with an IC50 value of 22.8 nM in Karpas 299 human non-Hodgkin’s Ki-positive large cell lymphoma carrying the NPM-ALK fusion gene and 26 nM in Ba/F3 cells transfected with the NPM-ALK fusion gene. Ceritinib also shows good selectivity over wild-type Ba/F3 cells (IC50>2 μM) and Ba/F3 cells transfected with Tel-InsR gene (IC50=320 nM)[2].

[In Vivo]

Ceritinib (LDK378) has an excellent pharmacokinetics profile in rodents and non-rodents with an oral bioavailability of >50%. Ceritinib demonstrates dose-dependent tumor growth inhibition and achieved partial tumor regression in the Karpas 299 rat xenograft model with daily administration but is capable of achieving complete tumor regression in the H2228 NSCLC rat xenograft model, which carries the EML4-ALK fusion gene. In both models, Ceritinib (LDK378) is well tolerated in animals. Ceritinib (LDK378) is further assessed for its ADME profile and is found to have a relatively good metabolic stability in liver microsomes, modest CYP3A4 inhibition, some hERG inhibition with an IC50 value of 46 μM in hERG patch clamp experiments, but no evidence of QTc prolongation in both dog and monkey telemetry studies[2].

[Animal admin]

In vivo PK studies are conducted in mice, rats, dogs, and cynomolgus monkeys. Ceritinib (LDK378) (HCl salt) is administered to male Balb/c mice intravenously via tail vein at 5 mg/kg (n=3) and orally via gavage at 20 mg/kg (n=3). By use of the same formulation, Ceritinib (LDK378) (HCl salt) is dosed to Sprague-Dawley rats intravenously via the tail vein at 3 mg/kg (n=3) and orally via gavage at 10 mg/kg (n=3). Blood samples are collected serially at scheduled times over 24 h after dosing. Male beagle dogs receive a single intravenous (n=2) or oral (n=3) dose of Ceritinib (phosphate salt) as an intravenous solution at 5 mg/kg and an oral suspension at 20 mg/kg, respectively. Male cynomologus monkeys receive single intravenous (n=2) or oral (n=3) dose of Ceritinib (free base) as an intravenous solution at 5 mg/kg and an oral suspension at 60 mg/kg, respectively. Blood samples for plasma are collected at prescheduled times over 144 h after dosing[1].

[References]

[1]. Marsilje TH, 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

[2]. Chen J, et al. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem. 2013 Jul 25;56(14):5673-4.

[3]. Tucker ER, et al. Immunoassays for the quantification of ALK and phosphorylated ALK support the evaluation of on-target ALK inhibitors in neuroblastoma. Mol Oncol. 2017 Aug;11(8):996-1006.


[Related Small Molecules]

Insulin(human) | Brigatinib | lorlatinib | Alectinib (CH5424802) | OSI-906(Linsitinib) | Entrectinib | Insulin(cattle) | BMS-754807 | Picropodophyllotoxin | TAE684(NVP-TAE684) | NVP-AEW541 | BMS-536924 | AZD-3463 | NT157 | Repotrectinib

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
720.7±70.0 °C at 760 mmHg

[ Molecular Formula ]:
C28H36ClN5O3S

[ Molecular Weight ]:
558.135

[ Flash Point ]:
389.6±35.7 °C

[ Exact Mass ]:
557.222717

[ PSA ]:
116.85000

[ LogP ]:
5.03

[ Vapour Pressure ]:
0.0±2.3 mmHg at 25°C

[ Index of Refraction ]:
1.595

Safety Information

[ Hazard Codes ]:
Xi

Related Compounds