Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array

Dual specificity protein phosphatases (DSPases) are key regulators of signal transduction, oncogenesis and the cell cycle. Few potent or specific inhibitors of DSPases, however, are readily available for these pharmacological targets. We have used a combinatorial/parallel synthetic approach to rigidify the variable core region and modify the side chains of 4-(benzyl-(2-[2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl) butyric acid (or SC-alpha alpha delta 9), which is the most active element in a previously described library of phosphatase inhibitors (Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yokokawa, S.; Messner, D. J.; Boynton, A. L.; Wipf, P.; Late, J. S. Biochemistry 1997, 36, 15965). Several analogues were identified as effective inhibitors of the protein tyrosine phosphatase (PTPase) PTP1B and the DSPases VHR and Cdc25B(2). Two compounds, FY3-alpha alpha 09 and FY21-alpha alpha 09, were partial competitive inhibitors of Cdc25B(2) with K-i values of 7.6+/-0.5 and 1.6+/-0.2 mu M, respectively. FY21-alpha alpha 09 possessed only moderate activity against PTP1B. Consistent with its in vitro anti-phosphatase activity, FY21-alpha alpha 09 inhibited growth in MDA-MB-231 and MCF-7 human breast cancer cell lines. FY21-alpha alpha 09 also inhibited the G(2)/M transition in tsFT210 cells, consistent with Cdc25B inhibition. Several architectural requirements for DSPase inhibition were revealed through modification of the side chain moieties or variable core region of the pharmacophore, which resulted in decreased compound potency. The structure of FY21-alpha alpha 09 provides a useful platform from which additional potent and more highly selective phosphatase inhibitors might be generated. (C) 2000 Elsevier Science Ltd. All rights reserved.