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Questions And Answer

• Indications and Usage

  Ceritinib is a new ALK gene inhibitor (ALKi) developed by Novartis Pharmaceuticals; its commercial name is Zykadia, and its previous code was LDK378. It was approved by the FDA for sale on April 29, 2014, and it is used to treat anaplastic lymphoma kinase (ALK) positive transfer of crizotinib (CRZ) progress or intolerance of non-small cell lung cancer (NSCLC). ;

• Mechanisms of Action

  Crizotinib resistance is a major issue for patients undergoing treatment for ALK gene rearrangement positive non-small cell lung cancer. Ceritinib is a kind of ALK tyrosine kinase inhibitor. Ceritinib does not target the MET proto-oncogene, but instead inhibits the insulin-like growth factor 1 receptor and blocks proteins from promoting cancer cell development, thus inhibiting the expression of EML4-ALK and NPM-ALK fusion protein cells. It is used to treat ALK rearrangement positive NSCLC patients who have previously used Crizotinib and can overcome Crizotinib resistance. Compared to Crizotinib, Ceritinib does not inhibit MET kinase activity, but inhibits IGF-1 receptors. Whether in terms of enzyme reaction, cell analysis or Crizotinib resistant animal models, research results all show that Ceritinib is more effective than Crizotinib. Additionally, regardless of any ALK resistance mutation, Ceritinib is still highly effective. In clinical models, Ceritinib’s ALK inhibition has 20 times the tumor-fighting effect of Crizotinib. Ceritinib also has the same effect on Crizotinib resistant central nervous system lesion NSCLC. Clinical trials show that Ceritinib can effectively inhibit ALK targets, potentially affecting an unknown kinase related to drug resistance, thus overcoming Crizotinib resistance. ;

• Binding Mode

  Ceritinib is a type I inhibitor of ALK, and it binds similarly to crizotinib with the DFG-Asp in conformation (Fig. 3). The 2,4-diaminopyrimidine core forms two hydrogen bonds with Met1199 of the ALK hinge (Fig. 4). One of the sulfonyl oxygens forms a 6-membered intramolecular hydrogen bond with the adjacent amine, and this oxygen also interacts with the side chain amine of Lys1150 via a water molecule. The terminal 2-isopropoxy-3- (piperidin-4-yl) phenyl group resides between the solvent and the ATP-binding pocket.
  ;

• Patents

  American patent numbers: US7153964，US7893074，US7964592，US8039474，US8039479，US8377921，US8703787.
  Patent expiration dates:
  February 26, 2021 (US7153964)
  April 25, 2026 (US7893074)
  January 13, 2027 (US7964592)
  June 29, 2030 (US8039474, US8039479)
  November 20, 2027 (US8377921)
  April 29, 2032 (US8703787)
  Patents belong to Novartis ;

• Chemical Synthesis

  Ceritinib can be synthesized using a highly convergent synthetic route that consist two sequential amination reactions on 2,4,5-trichloropyrimidine itself (Scheme 6.1). In the first amination step, 2-(isopropylsulfonyl)aniline can be isolated in three steps from fluoronitrobenzene, and in the second step, 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline is easily isolated in four steps from 2-chloro-4-fluorotoluene. Overall yields are >28% from 2-fluoronitrobenzene and >22% from 2-chloro-4-fluorotoluene.
  
  Scheme 6.1 Synthesis of LDK378 (1, ceritinib). Reagents and conditions: (a) propane-2-thiol, K2CO3, DMF, 45°C ON. (b) NaBO3, AcOH, 60°C. (c) H2/Pd/C, EtOAc/MeOH (10/1). (d) NaH, DMF/DMSO, 0–20 °C. (e) KNO3, H2SO4, 0–20°C. (f ) IPA, Cs2CO3, 60°C, 24 h. (g) 4-Pyridineboronic acid, 1-BuOH (Pd2(dba)3, 2-dicyclohexylphosphine-2′-6′-dimethoxy biphenyl, MW, 150 °C. (h) AcOH/TFA; PtO2, H2, RT, 3 h. (i) Anh. HCl-dioxane, 0.1M anh. 2-methoxy ethanol, 135 °C, 2 h. ;

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