Discovery of biarylaminoquinazolines as novel tubulin polymerization inhibitors

  • J Med Chem. 2014 Jun 12;57(11):4598-4605. doi: 10.1021/jm500034j.
Giovanni Marzaro  #  1 ,  Antonio Coluccia  #  2 ,  Alessandro Ferrarese  1 ,  Paola Brun  3 ,  Ignazio Castagliuolo  3 ,  Maria Teresa Conconi  1 ,  Giuseppe La Regina  2 ,  Ruoli Bai  4 ,  Romano Silvestri  2 ,  Ernest Hamel  4 ,  Adriana Chilin  1
Affiliations
  • 1. Dipartimento di Scienze del Farmaco, Universitá degli Studi di Padova, via Marzolo 5, 35131 Padova, Italy.
  • 2. Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Universitá di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 3. Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121 Padova, Italy.
  • 4. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • # Contributed equally.
PMID: 24801610 DOI: 10.1021/jm500034j
Abstract

Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. Although compounds 1-3 acted as dual inhibitors, the heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. Furthermore, molecular modeling studies allowed the rationalization of the pharmacodynamic properties of the compounds.