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Design, Synthesis, and Biological Evaluation of 6‑Substituted Thieno[3,2‑d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

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posted on 11.01.2019, 00:00 by Romeo Romagnoli, Filippo Prencipe, Paola Oliva, Stefania Baraldi, Pier Giovanni Baraldi, Santiago Schiaffino Ortega, Mariem Chayah, Maria Kimatrai Salvador, Luisa Carlota Lopez-Cara, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Roberto Ronca, Roberta Bortolozzi, Elena Mariotto, Elena Mattiuzzo, Giampietro Viola
The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)­thieno­[3,2-d]­pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)­thieno­[3,2-d]­pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.

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