Cathepsin D is a lysosomal aspartic protease found in all mammalian cells and is considered to be one of the main catabolic proteinases. It is synthesized as an inactive proenzyme of MW 52 kDa, called procathepsin D. Its activation involves the removal of a 44 amino acid peptide chain. Cathepsin D has been suggested to play a role in the metastatic potential of several types of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. In fact cathepsin D levels have recently been used as a marker to predict the prognosis of breast cancer and uterine cancer patients. The design, via computer molecular modeling, and the synthesis of (hydroxyethyl)amine isostere inhibitors that are similar to potent inhibitors of the aspartyl HIV-1 protease is proposed. The compounds will be evaluated for their inhibition of cathepsin D using appropriate esterase and proteinase assays. Detailed kinetic studies will then be performed and structure-activity correlations will be drawn for the synthetic inhibitors. This project is designed as a research effort, which will allow undergraduate students training in molecular modeling, organic synthesis, instrumental techniques, enzyme assays, kinetic studies, and statistical treatment of data through the enhancement of the research environment at this undergraduate institution.
|McConnell, Rose M; Inapudi, Kalyani; Kadasala, Naveen et al. (2012) New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines. Med Chem 8:1146-54|