Ceritinib

Ceritinib is a second-generation, orally bioavailable ALK tyrosine kinase inhibitor developed for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). As a highly potent and selective ALK inhibitor (IC₅₀ = 0.2 nM), 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 also displays potent inhibition of insulin receptor (IR), insulin-like growth factor receptor 1 (IGF1R), serine/threonine-protein kinase STK22D, and FLT3 (IC₅₀ values are 7, 8, 23, and 60 nM, respectively). Ceritinib is supplied as a white to off-white solid powder with a melting point of 172–177 °C. In quality control contexts, Ceritinib serves as a primary reference standard for analytical method development, method validation, and impurity profiling of ceritinib-containing drug products. The compound's related substances are recognized as critical quality attributes requiring strict control during commercial manufacturing. Ceritinib represents a significant therapeutic advancement in ALK-positive NSCLC, offering a treatment option for patients who have developed resistance to first-generation ALK inhibitors, with a surprisingly high response rate of 56% towards crizotinib-resistant tumors. The structural complexity and therapeutic importance of Ceritinib make it an essential API and reference material for pharmaceutical manufacturers and analytical laboratories worldwide.

 

Product Parameters

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Parameter	Specification
Product Name	Ceritinib
CAS Number	1032900-25-6
Molecular Formula	C₂₈H₃₆ClN₅O₃S
Molecular Weight	558.14 g/mol
Appearance	White to off-white solid powder
Melting Point	173–175 °C
Boiling Point	720.7 ± 70.0 °C (predicted)
Density	1.251 ± 0.06 g/cm³ (predicted)

 

Mechanism Of A ction

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Ceritinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks protein activity to inhibit cancer cell progression, specifically targeting cells expressing the EML4-ALK or NPM-ALK fusion proteins. It is indicated for metastatic ALK-positive NSCLC patients who have previously received crizotinib treatment, enabling overcoming crizotinib resistance. Compared to crizotinib, ceritinib does not inhibit MET kinase activity but instead suppresses the IGF-1 (insulin-like growth factor 1) receptor.

 

Synthetic Route

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Ceritinib is indicated for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have experienced disease progression after crizotinib therapy or are intolerant to crizotinib. Ceritinib is synthesized via a convergent approach: two fragments with similar molecular weights are first prepared and then joined together. The first fragment is derived from compound 1; after nitration, it undergoes an SNAr reaction with isopropanol to yield compounds 2 and 3, which are subsequently coupled via Suzuki coupling, followed by hydrogenation-reduction of the nitro group under PtO₂ catalysis to form salt compound 4. The second fragment is derived from compound 5; it undergoes an SNAr reaction with isothioprene, followed by oxidation of the thioether to a砜, and subsequent reduction of the nitro group to yield compounds 6 and 7, which react via an SNAr to form compound 8. It should be noted that compound 7 contains three chlorine atoms; in SNAr reactions, the reactivity of the 4-position chlorine is significantly greater than that of the 2-position chlorine and far greater than that of the 5-position chlorine, depending on the presence of electron-withdrawing groups at the ortho or para positions. Compound 8 represents the second fragment, which reacts with compound 4 via an SNAr followed by alkaline neutralization to yield ceritinib. The design of the SNAr reaction between compounds 8 and 4 is highly sophisticated: secondary fatty amines generally exhibit higher nucleophilicity than anilines; in compound 4, the secondary amine forms a chloride salt, significantly reducing its reactivity, thus ensuring an aniline-based reaction rather than a reaction involving a secondary fatty amine.

 

Untoward Effect

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The tolerability of oral ceritinib in patients with advanced NSCLC is predictable and manageable. Treatment-related adverse events occurred in 97% to 100% of ceritinib-treated subjects. In the ASCEND-1, ASCEND-2, and ASCEND-4 trials, the most common adverse events (occurrence rate>40%) among ceritinib-treated subjects were diarrhea (80%–87%), nausea (69%–83%), and vomiting (61%–66%). The most frequently reported grade 3–4 adverse events (occurrence rate ≥5%) included elevated transaminases [alanine aminotransferase (ALT): 17%–31%; aspartate aminotransferase (AST): 5%–17%) and diarrhea (5%–6%). Ceritinib-related adverse events were typically grade 1–2, could be alleviated by discontinuing or reducing the dose, and rarely (2%) led to treatment discontinuation. The incidence rates of adverse events were compared between the ceritinib group and the chemotherapy group in ASCEND-4: the higher incidences in the ceritinib group included diarrhea (85%), nausea (69%), vomiting (66%), and elevated transaminases (ALT: 60%; AST: 53%), whereas anemia (35%) was more prevalent in the chemotherapy group.

 

Contact Us

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Securing Ceritinib for your ALK inhibitor manufacturing campaign, impurity profiling program, or analytical method development should be straightforward. Cosperpharm makes it simple with high-quality reference standards, comprehensive documentation, and responsive technical support. Contact us today to discuss your requirements—we're here to help you succeed.