Abstract 2543: PRLX 93936, is a potent, novel, tumor-selective, small molecule with a unique mechanism of action

Abstract

Abstract Currently in Phase I testing, PRLX 93936 was developed and characterized at Prolexys Pharmaceuticals. It is a potent small molecule drug that shows robust and selective anti-cancer activity in a wide array of solid tumors including those with mutations that activate the RAS pathway. PRLX 93936 was chosen as a clinical lead as a result of extensive medicinal chemistry efforts and pharmacological profiling of over 400 novel small molecules. These compounds were designed to cover the chemical space originating from a molecule, Erastin, identified in a screen against isogenic cell lines differentially expressing genes such as those that activate the RAS pathway (Dolma et. al, Cancer Cell 3: 285-296, 2003). Cells that are sensitive to PRLX 93936 undergo caspase dependent apoptosis, necrosis, cell cycle arrest, ion flux and cell shrinkage leading to death and tumor growth inhibition. Characterization of drug treated cells shows that selective activation of RAS and JNK pathway members correlates with compound sensitivity. Research to elucidate the precise mechanism(s) and target(s) through which these biological responses are achieved has revealed that PRLX 93936's mechanism of action is unique. Several key lines of evidence support this conclusion including: 1. COMPARE analysis of PRLX 93936 activity in the NCI 60 panel of cell lines which showed that it is functionally distinct among the agents tested, 2. Profiling studies which examined PRLX 93936 binding or inhibition of enzyme activity against CYP450 enzymes, cell surface receptors and action potential mediating cardiac ion channels revealed only Cyp 3A4 and hERG as potential targets, 3. Kinase profiling of PRLX 93936 against evolutionarily diverse enzymes which identified no significant inhibitory activity, and 4. Genotyping and gene expression profiling studies which have yet to reveal a clear target profile correlation. Since the most common target classes were eliminated as potential suspects, additional non-traditional enzyme targets were screened for relevance to PRLX 93936 activity. Proteomics experiments identified the mitochondrial protein VDAC (Voltage Dependent Anion Channel) as a specific binding protein and potential molecular target of PRLX 93936 (Yagoda et al., Nature. 447: 865-869, 2007). More recent findings indicate that PRLX 93936 is a potent, selective inhibitor of several RAS pathway proteins including key enzymes which regulate the phosphorylation and activity of proteins involved in the RAS/JNK pathway. RNAi based validation studies and synergistic anti-cancer activity observed in combination with specific targeted drugs support these findings. PRLX 93936 may therefore represent a novel class of cancer therapeutics that target the majority of tumors characterized by RAS pathway activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2543.