Research Project
9141331
? DESCRIPTION (provided by applicant): Mutations in the ras family of genes were first identified in human cancer over 30 years ago. Such mutations result in the constitutive activation of one or more of three major Ras protein isoforms, including H-Ras, N-Ras, or K-Ras, that mediate important signaling pathways leading to uncontrolled cell growth and tumor development. Activating ras gene mutations occur de novo in approximately one third of all human cancers and are especially prevalent in colorectal, lung, and pancreatic tumors. Mutations in ras also arise in tumors that become resistant to chemotherapy and/or radiation. Currently there are no available drugs approved by the U.S. Food and Drug Administration that can selectively suppress the growth of tumors driven by activated Ras. From a phenotypic assay involving high-throughput screening, ADT Pharmaceuticals Inc. has discovered a novel compound series that potently and selectively inhibit tumor cells harboring activated Ras. Following extensive chemical optimization, a preclinical development candidate, DC070-547, was identified that shows low nanomolar growth inhibitory IC50 values in tumor cells having activated Ras while tumor cells lacking activated Ras, and cells derived from normal tissues, are essentially insensitive. The mechanism appears to involve direct binding within the catalytic domain of Ras to disrupt Ras-Raf interactions. Although DC070-547 shows evidence of in vivo antitumor activity in mouse xenograft models, the compound is rapidly metabolized by glucuronidation at a phenolic hydroxyl site within the molecule. We therefore propose a prodrug approach to improve the metabolic stability of DC070-547. Aim 1 will synthesize and characterize the metabolic stability of 12 unique prodrug forms of DC070-547. Aim 2 will evaluate the pharmacokinetics of candidate prodrugs in mice and will measure the levels of unchanged prodrug, as well as any active or inactive metabolites in plasma and tissues. Aim 3 will determine in vivo tolerance and antitumor activity of candidate prodrugs in xenograft models. We anticipate a clinical development candidate will emerge from this project that will be advanced to a phase II SBIR application involving GMP scale-up synthesis and GLP toxicity testing to support an IND application for human clinical trials in patients with Ras-driven cancers.
