Name: Ceritinib
Brand: BOC Sciences
Price: 298 USD
Availability: MadeToOrder

Purity

≥98%

Solubility

Soluble in DMSO.

Appearance

Solid Powder

Application

Antineoplastic Agents

Storage

Store at -20°C

IUPACName

5-chloro-2-N-(5-methyl-4-piperidin-4-yl-2-propan-2-yloxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine

Synonyms

5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine, LDK-378, LDK378; LDK 378; Zykadia; NVP-LDK378-NX

InChI Key

VERWOWGGCGHDQE-UHFFFAOYSA-N

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)

Canonical SMILES

CC1=CC(=C(C=C1C2CCNCC2)OC(C)C)NC3=NC=C(C(=N3)NC4=CC=CC=C4S(=O)(=O)C(C)C)Cl

1.Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.

Schaefer ES1, Baik C2. Cancer Manag Res. 2016 Mar 24;8:33-8. doi: 10.2147/CMAR.S96471. eCollection 2016.

Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%-7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose.

2.Successful treatment with ceritinib after crizotinib induced hepatitis.

Sassier M1, Mennecier B2, Gschwend A2, Rein M3, Coquerel A4, Humbert X5, Alexandre J4, Fedrizzi S4, Gervais R6. Lung Cancer. 2016 May;95:15-6. doi: 10.1016/j.lungcan.2016.02.008. Epub 2016 Feb 23.

We report two cases of acute hepatitis induced by crizotinib in patients with ALK-rearranged non-small cell lung cancer (NSCLC) who were treated after by a second generation of ALK inhibitor without any incident. These cases suggest that ceritinib could be used as an alternative agent when crizotinib is responsible for hepatitis.

3.Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

Dong X1, Fernandez-Salas E2, Li E3, Wang S4. Neoplasia. 2016 Mar;18(3):162-71. doi: 10.1016/j.neo.2016.02.001.

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	1.7917 mL	8.9583 mL	17.9167 mL
5 mM	0.3583 mL	1.7917 mL	3.5833 mL
10 mM	0.1792 mL	0.8958 mL	1.7917 mL
50 mM	-	-	-

Dear Sirs, Can you explain the mechanism of action of Ceritinib?

Yes, I can! Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats.

22/7/2016

What is the activity of Ceritinib in vitro? Thank you very much in advance.

No thanks! Ceritinib shows good selectivity over wild-type Ba/F3 cells (IC50>2 μM) and Ba/F3 cells transfected with Tel-InsR gene (IC50=320 nM).

20/4/2017

Hello! And What is the activity of Ceritinib in vivo?

Hi, 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.

20/2/2020

retain high potency against the ALK enzymatic activity

Ceritinib 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. Working out great!

8/1/2019

antiproliferative activity

Ceritinib 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. The effect expected was seen with it!

4/2/2019

inhibit ALK activity

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. It worked well without trouble.

1/4/2020

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