Development of novel substituted naphthyl amino benzoic acid derivatives as CDC25 phosphatase inhibitors: design, synthesis and biological evaluation

Cell division cycle 25 (CDC25) proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach [1]. Recently, we identified compound 19 (NSC 28620) as a novel inhibitor of CDC25 phosphatase via a structure-based virtual screening approach [2]. This compound displayed reversible inhibition kinetics with in vitro Ki values for CDC25A and -B of 2.3 and 5.3 μM, respectively. To obtain a structural insight into the molecular properties of this new type of CDC25 phosphatase inhibitor and to optimize its potential, herein, computer-assisted optimization of the initial hit 19 by synthesis and preliminary screening of a focused compound library led to the identification of a set of 24 novel derivatives. Among them, 15 compounds showed notable inhibitory activity against CDC25B. The most efficient ones in this subset, i.e. 5, 10-13, 20 and 23, improved the potency compared to hit 19, as evaluated through the IC50 values. In order to provide insight into the binding mechanism of the designed compounds, we adopted the relaxed complex scheme (RCS) method, an advanced computer-docking methodology that accounts for protein receptor flexibility using molecular dynamics simulations. References 1. Lavecchia, A. et al. CDC25A and B dual-specificity phosphatase inhibitors: potential agents for cancer therapy. Curr. Med. Chem. 2009, 15, 1831–1849. 2. Lavecchia, A. et al. Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening. J. Med. Chem. 2012, 9, 4142-4158.