Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide

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 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1s), a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis. To assess ICA-1s as a possible therapeutic, in-vivo studies using a murine model were performed. ICA-1s was tested for stability in blood serum and results demonstrated that ICA-1s was stable in human plasma at 25 and 37°C over a course of 2 h. Toxicity of ICA-1s was tested for both acute and subacute exposure. The acute exposure showed patient surviving after 48 h of doses ranging from 5 to 5000 mg/kg. Subacute tests exposed the patients to 14 days of treatment and were followed by serum and tissue collection. Aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, troponin, and C-reactive protein serum levels were measured to assess organ function. ICA-1s in plasma serum was measured over the course of 24 h for both oral and intravenous treatments. Heart, liver, kidney, and brain tissues were analyzed for accumulation of ICA-1s. Finally, athymic nude mice were xenografted with DU-145 prostate cancer cells. After tumors reached ~0.2 cm2, they were either treated with ICA-1s or left as control and measured for 30 days or until the tumor reached 2 cm2. Results showed tumors in treated mice grew at almost half the rate as untreated tumors, showing a significant reduction in growth. In conclusion, ICA-1s is stable, shows low toxicity, and is a potential therapeutic for prostate carcinoma tumors.

Atypical Protein Kinase C Hyperactivity in Insulin-Resistant and Insulin-Sensitive Forms of Alzheimer’s Disease: A Potential Therapeutic Target

“…Thus, in insulin-resistant, hyperinsulinemic states, these agents can reduce brain aPKC activity (i) at lower doses, indirectly via inhibition of liver aPKC and reduction of blood insulin levels, and (ii) at higher doses, by directly inhibiting brain aPKC. In this regard, note that, in published (38) and other pharmacokinetic/pharmacodynamic (PK/PD) studies, it was found that ICAP preferentially distributes to liver, but clearly passes the BBB to enter the brain. And, as found in other studies, ICAP is effective in liver and brain when given insufficiently increased doses by oral gavage (i.e., per os [PO]), as well when administered IV or SC.…”

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

“…PKCζ expression is positively correlated with poor overall survival in prostate cancer [ 289 ]. Inhibitors of PKCζ and λ/ι are therapeutic molecules for prostate cancer [ 290 , 291 , 292 , 293 ]. For example, treatment with the aPKC inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and ICA-1 significantly decreased malignant cell proliferation and induced apoptosis [ 290 , 291 ].…”

“…Inhibitors of PKCζ and λ/ι are therapeutic molecules for prostate cancer [ 290 , 291 , 292 , 293 ]. For example, treatment with the aPKC inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and ICA-1 significantly decreased malignant cell proliferation and induced apoptosis [ 290 , 291 ]. Furthermore, inhibition of aPKCs attenuates prostate cancer cell metastasis by downregulating vimentin expression [ 293 ].…”

aPKC in neuronal differentiation, maturation and function

“…The same group also characterized a PRKCI selective inhibitor 5-amino-1-(1R,2S,3S,4R)-2,3-dihydro xy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide [67,68]. This compound has been tested in murine models [69]. Importantly, this inhibitor does not inhibit PRKCZ at concentrations up to 5 μM [67].…”