Structure-based discovery of novel non-nucleosidic DNA alkyltransferase inhibitors: virtual screening and in vitro and in vivo activities

11 páginas, 6 figuras, 2 tablasThe human DNA-repair O (6)-alkylguanine DNA alkyltransferase (MGMT or hAGT) protein protects DNA from environmental alkylating agents and also plays an important role in tumor resistance to chemotherapy treatment. Available inhibitors, based on pseudosubstrate analogs, have been shown to induce substantial bone marrow toxicity in vivo. These deficiencies and the important role of MGMT as a resistance mechanism in the treatment of some tumors with dismal prognosis like glioblastoma multiforme, the most common and lethal primary malignant brain tumor, are increasing the attention toward the development of improved MGMT inhibitors. Here, we report the identification for the first time of novel non-nucleosidic MGMT inhibitors by using docking and virtual screening techniques. The discovered compounds are shown to be active in both in vitro and in vivo cellular assays, with activities in the low to medium micromolar range. The chemical structures of these new compounds can be classified into two families according to their chemical architecture. The first family corresponds to quinolinone derivatives, while the second is formed by alkylphenyl-triazolo-pyrimidine derivatives. The predicted inhibitor protein interactions suggest that the inhibitor binding mode mimics the complex between the excised, flipped out damaged base and MGMT. This study opens the door to the development of a new generation of MGMT inhibitors.Work was partially supported by a grant from the “Comunidad de Madrid” (SBIO-0214-2006). Work at CNIO was supported by grants from “Fondo de Investigaciones Sanitarias” FIS (PI030989) and the Education and Science Ministry of Spain (GEN2003-20642-C09-02/NAC). Work at CBMSO was supported by grants from the Education and Science Ministry of Spain (BIO2005-0576 and GEN2003-206420-C09-08), Comunidad de Madrid (200520M157) and by an institutional grant from the Ramón Areces Foundation. Generous allocation of computer time at the Barcelona Supercomputer Center is gratefully acknowledged. CF was supported by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (Spain). We thank Dr Susana Gonzalez for providing HTB-38 cells.Peer reviewe