Prlx 93936 displays anti-tumor activity in vitro and in vivo against multiple models of human tumors

5714 PRLX 93936 is a novel small molecule which exhibits therapeutic potential in a diverse array of in vitro and in vivo tumor models including examples with limited treatment options such as pancreatic cancer. Developed and characterized in cell-based phenotypic assays, PRLX 93936 is a product of extensive SAR work originating from a small molecule identified in a synthetic lethal screen against isogenic cell lines engineered to differentially express several genes including activated RasV12 (Dolma et.al, Cancer Cell 3: 285-296, 2003). A series of structural analogs were designed, synthesized and tested for antiproliferative activity against a panel of normal cell lines and lines derived from tumors with dissimilar causative mutations. The results indicate potent and selective activity against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas in addition to 100 and 1000 fold improvements in parameters such as potency and solubility respectively. In vivo test results in multiple tumor xenograft models mirrored the in vitro findings producing efficacy ranging from complete regression to tumor-growth inhibition in a dose-dependent manner following oral (PO), intravenous (IV), or intraperitoneal (IP) administration. In vivo efficacy testing of PRLX 93936 in parallel or in combination with other agents such as gemcitabine, bevacizumab, paclitaxel and irinotecan suggest that PRLX 93936 is an effective single agent but that its activity may be complemented by the presence of other drugs. Responsive in vivo tumor models include: HT1080 (fibrosarcoma), PANC-1 (pancreatic), OVCAR-5 (ovarian), DLD-1, Colo205 and HCT116 (colon), in addition to models of non small cell lung cancer, mesenchymal chondrosarcoma, leiomyosarcoma and multiple myeloma. Toxicology studies with mice, rats, dogs, and monkeys demonstrate drug tolerance at potentially therapeutic levels based on body surface area scaling. Although its mechanism of action is still under investigation, examination of the effects of compound treatment upon sensitive cells indicates that PRLX 93936 can rapidly affect ion flux, cell cycle, and mitochondrial membrane polarization ultimately inducing caspase dependent apoptosis. Mass spectrometry-based proteomics experiments indicate that both PRLX 93936 and its parent compound can bind to a mitochondrial protein VDAC (Voltage Dependent Anion Channel) which may be a molecular target (Yagoda et al., Nature. Jun 14;447(7146):864-8). Based on the results of the preclinical pharmacodynamic, pharmacokinetic and toxicological studies, Prolexys initiated Phase I studies with PRLX 93936 in August, 2007.