Synthesis and biological evaluation of novel pyrido[2,3-b]pyrazines inhibiting both erlotinib-sensitive and erlotinib-resistant cell lines.

A series of novel pyrido[2,3-b]pyrazines were synthesized as potential antitumor agents for erlotinib-resistant tumors. Known signal inhibitor compounds from our Nested Chemical Library were tested in phenotypic assays on erlotinib-sensitive PC9 and erlotinib-resistant PC9-ER cell lines to find a compound class to be active on erlotinib resistant cell lines. Based on the screening data, novel pyrido[2,3-b]pyrazines were designed and synthesized. The effect of the substituent position of the heteroaromatic moiety in position 7 and the importance of unsubstituted position 2 of the pyridopyrazine core were explored. Compound 7n had an IC50 value of 0.09 μM for the inhibition of PC9 and 0.15 μM for the inhibition of PC9-ER. We found that some lead compounds of these structures overcome erlotinib-resistance which might become promising drug candidates to fight against NSCLC with EGFR T790M mutation. The signaling network(s) involved in the mechanism(s) of action of these novel compounds in overcoming erlotinib resistance remain to be elucidated.
AuthorsLászló Kékesi, Anna Sipos, Gábor Németh, János Pató, Nóra Breza, Ferenc Baska, László Őrfi, György Kéri
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 22 Pg. 6152-5 (Nov 15 2013) ISSN: 1464-3405 [Electronic] England
PMID24095095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazines
  • Quinazolines
  • Erlotinib Hydrochloride
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Carcinoma, Non-Small-Cell Lung (drug therapy)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Erlotinib Hydrochloride
  • Humans
  • Lung Neoplasms (drug therapy)
  • Protein Kinase Inhibitors (pharmacology)
  • Pyrazines (chemical synthesis, chemistry, pharmacology)
  • Quinazolines (pharmacology)
  • Signal Transduction

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