Lung cancer causes more deaths in men and women than any other cancer in the United States. Late detection of disease and inability to effectively treat this malignancy with chemotherapy are the main reasons for low survival rates. There is an urgent medical need to develop new molecularly targeted drugs for treating lung cancer, although it has been challenging to identify targets that are unique to cancer cells. This phase 1 SBIR application is based on an innovative technology platform being developed by PDEi Pharmaceuticals LLC stemming from the company's discovery that phosphodiesterase 10 (PDE10) is elevated in lung cancer and essential for the survival and proliferation of lung tumor cells. PDE10 plays a central role in signal transduction and is an attractive cancer target because it has low expression levels in peripheral tissues, but is strongly induced during cancer, whereby inhibitors have potential for high efficacy and low toxicity. From an extensive medicinal chemistry effort to develop novel PDE10 inhibitors, a series of indene derivatives were synthesized and found to selectively inhibit lung tumor cell growth in vitro. A lead compound, MCI-020 was identified with attractive oral bioavailability and ability to obtain high lung concentrations compared to other tissues and plasma. MCI-020 was well tolerated and highly efficacious in an orthotopic mouse model of lung cancer. Because of the potential to improve potency and target selectivity of MCI-020, we propose the following aims for lead optimization. Aim 1 will synthesize a series of novel indene derivatives chemically related to MCI-020 and will evaluate in vitro anticancer activity and selectivity for PDE10. Aim 2 will assess drug-like properties of the derivatives by determining pharmacokinetics, tissue distribution, and maximum tolerated dosage to select a lead compound. Aim 3 will determine efficacy and toxicity of the lead compound in an orthotopic mouse model of lung cancer and will confirm mechanism of action using tissues from the mouse model. We anticipate a clinical candidate will result from this project that will be advanced to a phase II application involving GMP scale-up synthesis and GLP toxicity testing in support of an IND application for human clinical trials.
Public Health Relevance Statement: Public Health Relevance: Lung cancer is the second most prevalent cancer in men and women of all races in the United States and is by far the most lethal malignancy, causing more deaths than colon, prostate and breast cancer combined. There is an unmet medical need to develop more effective and less toxic drugs for lung cancer, but it has been challenging to identify targets unique to cancer cells. PDEi Pharmaceuticals LLC has discovered that an important regulatory enzyme, phosphodiesterase 10 (PDE10) is induced during lung cancer and essential for tumor cell survival and proliferation. Building on a well-defined chemical scaffold fr synthesizing new PDE10 inhibitors, the company has identified a prototype drug referred to as MCI-020 that shows promising drug-like properties and anticancer activity in a mouse model of lung cancer. Further development is needed to optimize for potency and target selectivity of MCI-020 to identify a candidate drug for clinical trials.
Project Terms: A549; absorption; Adenocarcinoma Cell; Alabama; analog; anticancer activity; Apoptosis; Autopsy; base; beta catenin; Biological; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; cancer cell; Cancer cell line; Cancer Etiology; caspase-3; cell growth; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; chemotherapy; Clinical; Clinical Trials; Colon Carcinoma; Cyclic GMP; Cyclin D1; design; Detection; Development; Disease; dosage; Dose; drug candidate; Drug Kinetics; Drug or chemical Tissue Distribution; Drug Targeting; Ensure; Enzyme Kinetics; Enzymes; Epithelial Cells; expression vector; Goals; Growth; Histopathology; Human; Image; Immunohistochemistry; improved; In Vitro; in vivo; Indenes; inhibitor/antagonist; innovative technologies; Institutes; Isoenzymes; Lead; Luciferases; Lung; Lung Adenocarcinoma; Lung Neoplasms; malignant breast neoplasm; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant Neoplasms; Measures; Medical; men; Metabolic; molecular modeling; Molecular Models; Molecular Target; Monitor; mouse model; Mus; neoplastic cell; novel; Oncogenic; Oral; Oral Administration; Organ; Patients; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; phosphoric diester hydrolase; Plasma; Play; pre-clinical; programs; Proliferation Marker; Property; prototype; public health relevance; Race; Respiratory physiology; Role; scaffold; scale up; screening; Series; Serum; Signal Transduction; Small Business Innovation Research Grant; stem; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Survival Rate; survivin; Tissues; Toxic effect; Toxicity Tests; treatment effect; Treatment Protocols; tumor; Tumor Cell Line; tumor growth; United States; Universities; vasodilator-stimulated phosphoprotein; Weight Gain; Woman
