Research Project
9409488
Mutations in the ras family of genes were first identified in human cancer over 30 years ago. Such mutations may result in the constitutive activation of one or more of three major Ras protein isoforms, including H-Ras, NRas, or K-Ras, that mediate important signaling pathways leading to uncontrolled cell growth and tumor development. Activating mutations of ras genes 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. Employing a cell-based phenotypic screen, ADT Pharmaceuticals Inc. has discovered a novel compound series that potently and selectively inhibits 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 harboring activated Ras, while tumor cells lacking activated Ras, and cells derived from normal tissues, are insensitive. Data suggest that the drug interacts with Ras to disrupt Ras-Raf interactions and suppress downstream signaling of both the Raf/MAPK and PI3K/Akt pathways. DC070-547 shows strong in vivo antitumor activity in a mouse xenograft model following i.p. administration with no discernible toxicity and attractive drug-like properties feasible for oral delivery. Here we propose to develop an oral formulation to enable further preclinical development and will work closely with Catalent, Inc., a company with extensive formulation expertise. Aim 1 will synthesize DC070-547 in bulk and extensively characterize the physiochemical properties of the compound in pre-formulation studies. Aim 2 will develop at least 4 unique formulations of DC070-547 and Aim 3 will determine the in vivo pharmacokinetic characteristics of the formulations and will select a final dose to be evaluated for tolerability in mice. We anticipate a clinical development candidate in an optimal formulation for oral delivery will emerge from this project that will be advanced to a Phase II SBIR application involving further preclinical development to optimize dose and schedule, GMP scale-up synthesis, and GLP toxicity assessment to support an IND application for human clinical trials in patients with Ras-driven cancers.
