Abstract 1416: Development and initial evaluation of the antitumor activity of a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L

The discovery of new chemotherapeutic strategies for inhibiting the growth and spread of cancer represents an important goal in the effort to enhance both cancer patient quality of life and survival. Cysteine cathepsins are a family of lysosomal proteases that are often upregulated in a variety of cancers and have been implicated in key processes in cancer progression. Our focus has centered on the development of novel non-peptidic inhibitors of cathepsin L. Small molecule inhibitors of the cysteine protease cathepsin L have the potential to limit degradation of extracellular matrix in the normal tissue surrounding the tumor thus retarding cancer metastasis. It has also been established that cathepsin L is involved in blood vessel development and thus inhibitors have the potential to suppress tumor growth and dissemination through an antiangiogenic effect. We have recently reported the synthesis of a series of functionalized benzophenone, thiophene, pyridine, and fluorene thiosemicarbazone derivatives several of which are potent inhibitors of cathepsin L with activity in the nM range while exhibiting IC50 values greater than 10 micromolar for cathepsin B. In addition, selected compounds were found to inhibit the migration, and invasion of DU-145 prostate cancer cells through Matrigel. Initial evaluation of the in vivo activity of the lead compound, designated KGP94, has been undertaken in a C3H mammary carcinoma. We have evaluated the effects of five daily doses of 20 mg/kg given to mice with treatment initiated either on the day of tumor inoculation or once the tumors reached 200 mm3 in size. Results to date indicate significant growth retardation is achieved against recently implanted and established tumors. Based on these encouraging results further work with this compound is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2011-1416