Synthesis and biological evaluation of novel pyrido[2,3-b]pyrazines inhibiting both erlotinib-sensitive and erlotinib-resistant cell lines |
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Authors: | László Kékesi Anna Sipos Gábor Németh János Pató Nóra Breza Ferenc Baska László ?rfi György Kéri |
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Institution: | 1. Vichem Chemie Research Ltd., Herman Ottó u. 15., H-1022 Budapest, Hungary;2. Rational Drug Design Laboratory CRC, Semmelweis University, POB 131, H-1367 Budapest 5., Hungary;3. Department of Pharmaceutical Chemistry, Semmelweis University, H?gyes Endre u. 9., H-1092 Budapest, Hungary;4. Pathobiochemistry Research Group of Hungarian Academy of Sciences in Department of Medical Chemistry, Semmelweis University School of Medicine, H-1085, T?zoltó u. 37-47., Budapest, Hungary |
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Abstract: | A series of novel pyrido2,3-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 pyrido2,3-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. |
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Keywords: | Erlotinib resistance Phenotypic screen PC9 PC9-ER Inhibitor |
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