Discovery and preclinical evaluation of a pyrroloquinoxaline based broad-spectrum anticancer agent

During the last decade, we have designed and synthesized several compounds endowed with cytotoxic properties. Among those compounds, a series of pyrroloquinoxaline derivatives, showing desirable drug-like properties and promising anticancer activity, have been identified.3 Some of the synthesized compounds showed an interesting profile at sub-micromolar concentrations in vitro assays in a wide panel of tumor cell lines. In particular, one of the most active compounds (SC144) has been selected for an in depth biological investigation. An excellent in vivo anti-cancer efficacy was ascertained for such a derivative by studies on xenograft mice, while flow cytometry studies indicated its capability to arrest cell cycle progression at the G0/G1 phase. Further mechanistic investigation revealed that our compound is able to induce reactive oxygen species by inhibition of Mn-SOD. The compound showed a synergistic effect when used in combination with several conventional cytotoxic agents. SC144 was also shown able to up-regulate MDA-7/IL-24 in colon cancer cells and also to induce gp130 phosphorylation-deglycosylation in ovarian cancer. The therapeutic potential of this compound was supported by its oral bioavailability assessed in a mouse model of human ovarian cancer, in which tumor growth was suppressed without significant evidence of toxicity. SC144 has been recently marketed, for research purposes only. [1] F. Grande, R. Yamada, X. Cao, F. Aiello, A. Garofalo, N. Neamati Expert Opin. Inv. Drug, 2009, 18, 555-568. [2] S. Xu, F. Grande, A. Garofalo, N. Neamati Mol. Cancer Ther. 2013, 12, 937-949.