Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1): A potent protein kinase C-I inhibitor as a potential anticancer drug

Abstract Protein Kinase C iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma and glioma. Previous In- vitro studies have shown that ICA-1 a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis {Pillai et al. Int. J. Biochem. Cell Biol. 43 (2011) 784-794. To assess ICA-1 as a possible therapeutic, In- vivo studies using a murine model were performed. ICA-1 was tested for stability in blood serum and results demonstrated that ICA-1 was stable in human plasma at 25oC and 37oC over a course of two hours. Toxicity of ICA-1 was tested for both acute and sub-acute exposure. The acute exposure showed subject surviving after 48 hours of doses ranging from 5mg/kg to 5000 mg/kg. Sub-acute tests exposed the subjects to 14 days of treatment and was followed by serum and tissue collection. AST, ALK-P, GGT, Troponin, and CR-P serum levels were measured to assess organ function. Heart, liver, kidney, and brain tissues were analyzed for accumulation of ICA-1. Finally athymic nude mice were xenografted with DU-145 prostate cancer cells. After tumors reached approximately 1 cm2, they were either treated with ICA-1 or left as control until the tumor reached 2 cm2. Results showed tumors in treated mice took almost double the time to reach the experimental end point, showing a significant growth reduction. In conclusion, ICA-1 is stable, shows low toxicity, and is a potential therapeutic for some carcinoma tumors. Citation Format: Christopher Apostolatos, Andre H. Apostolatos, Wishrawana S. Ratnayake, Marie Bourgeois, Mildred Acevedo-Duncan. Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1): A potent protein kinase C-ι inhibitor as a potential anticancer drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5868.