Clinical development of CX-3543, a novel multi-targeting antitumor agent

3206 Background: The targeting of cell signaling pathways as an effective therapeutic strategy has been validated by the emergence of new anticancer drugs such as the tyrosine kinase inhibitors. In a novel therapeutic approach, a G-quadruplex DNA motif found in the promoter regions of many well characterized oncogenes has been targeted by a synthetic small molecule, CX-3543. Methods: Medicinal chemistry efforts introduced drug-like moieties to achieve desirable DNA recognition and ADMET properties, and customized screening and molecular selectivity assays were used to confirm that CX-3543 selectively targets the parallel-type quadruplex with significant preference over other types of quadruplex conformations, or single stranded or duplex DNA. Results: Molecular selectivity assays have shown that CX-3543 targets the quadruplex structures found in the promoter regions of several major oncogenes, including VEGF, PDGF-Α, HIF-1α, H-Ras, c-Myc and others. In vitro tests conducted with CX-3543 have demonstrated ...