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 no significant inhibition of liver cytochrome P450 enzymes, very low metabolism when incubated with human hepatocytes, and no mutagenic effects in the Ames bacterial mutagenicity assay. CX-3543 displays favorable pharmacokinetic properties in mice, rats and dogs, and is well tolerated in murine xenograft models dosed at levels substantially higher than needed for an antitumor effect. Moreover, in vivo tests have shown that CX-3543 inhibits xenograft tumor growth in murine models of pancreatic cancer (MiaPaCa), refractory prostate cancer (PC3), and colorectal cancer (HCT-116). Conclusions: Phase I clinical testing of CX-3543 is planned for early 2005. Eligible cancer patients will be enrolled with tumors that are likely to be driven by the relevant oncogenes including certain lymphomas and colorectal, renal, lung, prostate, ovarian, pancreatic and breast cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cylene Cylene Cylene