Novel Ras inhibitor prodrug for colorectal cancer

DESCRIPTION provided by applicant Mutations in the ras family of genes were first identified in human cancer over 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 DC was identified that shows low nanomolar growth inhibitory IC 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 DC 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 DC Aim will synthesize and characterize the metabolic stability of unique prodrug forms of DC Aim 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 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 PUBLIC HEALTH RELEVANCE A high percentage of human cancers harbor activating mutations in the ras family of oncogenes that lead to the formation of abnormal Ras proteins giving rise to highly aggressive and drug resistant tumors for which there are no drugs approved by the FDA to treat Ras driven cancers ADT Pharmaceuticals Inc has discovered a novel class of Ras inhibitors and identified a preclinical drug development candidate DC that potently and selectively inhibits the growth of tumor cells with activated Ras While DC has attractive drug like properties and promising antitumor activity in mouse models of cancer further chemical optimization is necessary to improve the metabolic stability of DC using a prodrug approach which is expected to result in a highly effective and safe drug development candidate for clinical trials involving patients with Ras driven cancers such as certain colorecta pancreatic and lung cancers