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.
Public Health Relevance Statement: LAYPERSON SUMMARY A high percentage of human cancers harbor activating mutations in the ras family of oncogenes that lead to the formation of constitutively activated Ras proteins giving rise to highly aggressive and drug-resistant tumors. There are no drugs approved by the FDA to treat such Ras-driven cancers. ADT Pharmaceuticals Inc. has discovered a novel class of Ras inhibitors and identified a preclinical drug development candidate, DC070-547, that potently and selectively inhibits the growth of tumor cells harboring activated Ras. While DC070-547 has attractive drug-like properties and promising antitumor activity of the intraperitoneally administered drug in mouse models of cancer, an oral formulation of the drug is urgently needed to enable the progression of DC070-547 through pre-clinical studies and eventual clinical trials involving human patients with Ras-driven cancers, prominently including certain colorectal, pancreatic, and lung cancers. ADT Pharmaceuticals, Inc. will work closely with Catalent, Inc., a world-wide leader of drug formulation technology, to develop a pharmaceutically optimized formulation of DC070-547 suitable for clinical evaluation of the orally administered drug.
Project Terms: Address; Affinity; Alpha Cell; analog; base; Binding; Cancer Model; cell growth; Cells; Chemicals; chemotherapy; Clinic; clinical application; clinical development; Clinical Trials; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Dose; drug development; Drug Formulations; Drug Kinetics; Drug resistance; effective therapy; efficacy study; Evaluation; Excipients; FDA approved; Formulation; Future; Generations; Goals; Growth; Guanosine Triphosphate; Half-Life; HCT116 Cells; Histologic; HRAS gene; Human; improved; in vivo; Injection of therapeutic agent; intraperitoneal; Investigation; KRAS2 gene; Lead; Lipids; Lung Neoplasms; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant Neoplasms; MAP Kinase Gene; Mediating; Medical; mouse model; Mus; mutant; Mutation; nanomolar; National Cancer Institute; Neoplasm Metastasis; neoplastic cell; Normal tissue morphology; novel; novel therapeutic intervention; oncology; Oral; pancreatic neoplasm; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; pharmacokinetic characteristic; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; Plasma; preclinical development; Preclinical Drug Development; preclinical efficacy; preclinical study; Property; Protein Isoforms; Protocols documentation; Qualifying; Radiation; RAS Family Gene; ras Genes; Ras Inhibitor; ras Oncogene; ras Proteins; Ras/Raf; Receptor Protein-Tyrosine Kinases; research clinical testing; Resistance; scale up; Schedule; screening; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Solid; Solubility; Solvents; stability testing; Stress; success; Surface; Suspensions; Technology; Testing; Tissues; Toxic effect; tumor; Tumor Cell Line; tumor growth; tumorigenesis; uncontrolled cell growth; United States Food and Drug Administration; Water; Work; Xenograft Model
