Proteus syndrome is a rare segmental overgrowth disorder caused by a somatic gain of function mutation in the oncogene AKT1, encoding the AKT1 kinase. The disorder is progressive, with high morbidity and mortality there are very few living adults with this disease. Tissues and cell lines from patients with Proteus syndrome harbor admixtures of mutant alleles that ranged from <1% to approximately 50%. This mutation causes constitutive activation of AKT1, through Ser473 and Thr308 phosphorylation. This activation stimulates the AKT/PI3K pathway, mediating processes including increased cell proliferation and decreased apoptosis. The progressive nature of the disorder and the mechanism of disease (gain of function) make AKT1 an excellent target for therapeutics, specifically repression. The AKT/PI3K pathway is mutated in numerous cancers as well. Because it is commonly mutated in cancer, pharmaceutical companies are interested in targeting this molecule with inhibitors. Indeed, Proteus syndrome can be considered a simple model for cancer therapeutics, as these patients are known to harbor only a single activating mutation instead of the hundreds or thousands that are mutated in cancers. ArQule Inc. has developed a small molecule, ARQ 092 that effectively inhibits AKT, with the lowest IC(50) for AKT1 (as compared to AKT2 or AKT3, and orders of magnitude lower for other kinases). This agent has undergone significant development with animal toxicity studies and is currently in phase I trials in patients with different types of cancer. In addition, we have performed in vitro testing with ARQ 092 in cells from patients with Proteus syndrome and demonstrated reduction in AKT1 phosphorylation at doses in the range of achievable blood levels in humans with low toxicity. Because Proteus syndrome is a chronic disease, typical approaches to defining the recommended phase II dose by determining the maximum tolerated dose (MTD) are not appropriate - it is unreasonable to propose that patients would tolerate significant side effects for prolonged time periods. As an initial trial for this disease, we propose a phase I study to determine a recommended dose for subsequent trials, which will determine the efficacy of ARQ 092 in Proteus syndrome. The recommended phase II dose will be determined based on the tolerability of ARQ 092 in children and adults with Proteus syndrome and measures of drug levels in plasma and affected tissues in patients with Proteus syndrome and measures of tissue phosphorylation of AKT1. We hypothesize that the recommended dose of ARQ 092 will be substantially below that of doses used in patients with cancer and that this will lead to a highly favorable risk - benefit ratio on which we can base future efficacy studies.