A novel phosphodiesterase isozyme target and class of inhibitors for lung cancer

DESCRIPTION provided by applicant 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 SBIR application is based on an innovative technology platform being developed by PDEi Pharmaceuticals LLC stemming from the companyandapos s discovery that phosphodiesterase PDE is elevated in lung cancer and essential for the survival and proliferation of lung tumor cells PDE 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 PDE inhibitors a series of indene derivatives were synthesized and found to selectively inhibit lung tumor cell growth in vitro A lead compound MCI was identified with attractive oral bioavailability and ability to obtain high lung concentrations compared to other tissues and plasma MCI 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 we propose the following aims for lead optimization Aim will synthesize a series of novel indene derivatives chemically related to MCI and will evaluate in vitro anticancer activity and selectivity for PDE Aim will assess drug like properties of the derivatives by determining pharmacokinetics tissue distribution and maximum tolerated dosage to select a lead compound Aim 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 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 PDE is induced during lung cancer and essential for tumor cell survival and proliferation Building on a well defined chemical scaffold fr synthesizing new PDE inhibitors the company has identified a prototype drug referred to as MCI 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 to identify a candidate drug for clinical trials