Antitumor activity of a novel small molecule agent PRLX 93936 against human tumor xenograft models

B38 PRLX 93936 was identified as a potential anti-cancer therapeutic in a synthetic lethal screen against isogenic cell lines engineered to differentially express several oncogenes including activated RasV12. Subsequent testing against a series of normal and tumor cell lines derived from tumors with dissimilar causative mutations and limited treatment options, indicated potent and selective activity against a wide variety of tumor cell lines (many with activated Ras pathway). Mass spectrometric analysis of proteins selectively pulled-down from tumor lysates by PRLX 93936 immobilized on bead surfaces led to the identification of mitochondrial outer membrane protein VDAC (Voltage Dependent Anion Channel) as a potential target. PRLX 93936 caused tumor regression in human xenograft models representing cancers such as pancreatic (PANC-1) and fibrosarcoma (HT-1080). Tumor regression was demonstrated with oral (PO), intravenous (IV), and intraperitoneal (IP) routes of administration. In vivo, PRLX 93936 produces efficacy ranging from tumor-growth inhibition to complete regression in a dose-dependent fashion. Toxicology studies with mice, rats, dogs, and monkeys indicate drug tolerance at potentially therapeutic levels based on body surface area scaling. Although its mechanism of action is still under investigation, results of pharmacodynamic studies demonstrate its promise as a novel anti-cancer drug. As a result of successful IND submission, Phase 1 clinical trials are scheduled for September 2007.