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  2. Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy

Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy

  • Eur J Med Chem. 2019 Aug 15;176:393-409. doi: 10.1016/j.ejmech.2019.05.029.
Efthymios-Spyridon Gavriil 1 Aris Doukatas 2 Theodoros Karampelas 2 Vassilios Myrianthopoulos 1 Spyridon Dimitrakis 1 Emmanuel Mikros 1 Panagiotis Marakos 1 Constantin Tamvakopoulos 3 Nicole Pouli 4
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.
  • 2 Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece.
  • 3 Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. Electronic address: ctamvakop@bioacademy.gr.
  • 4 Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece. Electronic address: pouli@pharm.uoa.gr.
Abstract

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung Cancer cell line A549 and breast Cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.

Keywords

Breast cancer; EGFR inhibitors; Lapatinib; Non-small cell lung cancer; Pharmacokinetic studies; Purine analogues.

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