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.

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