Abstract 5071: KGP94, a small-molecule cathepsin L inhibitor with antitumor activity.

Abstract

Abstract Purpose: Cathepsins are a class of proteolytic enzymes recognized to play an important role in tumour progression, invasion and angiogenesis. The present study evaluated the anti-tumour activity of the small-molecule cathepsin L inhibitor KGP94 in a murine breast tumour model. Materials and Methods: Male CDF1 mice were inoculated on the right rear foot with a C3H mammary carcinoma. A solution of KGP94 was prepared each day by dissolving in a mixture of 10% Tween 80 and 90% HEPES-buffer. It was intraperitoneally injected at 0.01ml/g mouse bodyweight. Various doses (5-20mg/kg) were administered between 5-20 days, starting either from the day of tumour implant or when tumours had reached a volume of 200mm3. Tumour response was assessed by determining the tumour growth time, which was either the time in days to reach a volume of 500mm3 (TGT500) for animals treated from the day of tumour implant, or 1000mm3 (TGT1000) for animals treated when tumours were at a volume of 200mm3. Results are listed as Mean (± Standard Error). One-way ANOVA with a posthoc Student-Newman-Keuls comparison of group means was performed, and a P<0.05 was considered significant. Results: The TGT500 for control animals was 18.3 days (± 0.4). Treating tumours with 10mg/kg for 5 days significantly increased the TGT500 to 21.9 days (± 0.7). When the time of treatment with this dose was increased to 10 or 20 days, no additional growth inhibition was observed. Varying the drug dose for this 5 days treatment period showed that the TGT500 with 5mg/kg and 20mg/kg were 23.5 days (± 1.9) and 23.4 days (± 1.1), respectively. For experiments in which treatments were started when tumours had already reached 200mm3 an effect on TGT1000 was only observed with the highest drug dose at 20mg/kg; the respective TGT1000 being 5.9 days (± 0.2) for controls and 8.3 days (± 0.7) for KGP94. Conclusion: This synthetic, small-molecule cathepsin L inhibitor significantly delayed tumour growth, but the effect was primarily on the early phase following tumour inoculation. Such an effect suggests that KGP94 may have a role to play in inhibiting metastatic development rather than influencing the growth of established tumours. Supported by The Danish Cancer Society, The Danish Council for Independent Research: Medical Sciences, and OXiGENE Inc. Citation Format: Thomas Wittenborn, Mary Lynn Trawick, Kevin G. Pinney, David J. Chaplin, Dietmar W. Siemann, Michael R. Horsman. KGP94, a small-molecule cathepsin L inhibitor with antitumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2013-5071