piperidines and Adenomatous-Polyposis-Coli

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene through inhibition of cholesterol biosynthesis. Here, we report a medicinal chemistry evaluation of a collection of TASIN analogues and activity against colon cancer cell lines and an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of potent and selective analogues were identified, including compounds with good metabolic stability and pharmacokinetic properties. The compounds reported herein represent a first-in-class genotype-selective series that specifically target apc mutations present in the majority of CRC patients and serve as a translational platform toward a targeted therapy for colon cancer.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Drug Design; Drug Discovery; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred ICR; Mutation; Piperidines; Protein Binding; Structure-Activity Relationship; Sulfonamides

The human ether-à-go-go-related gene (hERG)1 K(+) channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apc(min/+) ) and azoxymethane (AOM)-treated mice. Colonic polyps of Apc(min/+) mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apc(min/+) showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis.

Topics: Adenomatous Polyposis Coli; Animals; Azoxymethane; Carcinogenesis; Carcinogens; Colorectal Neoplasms; Disease Models, Animal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; Intestine, Large; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Proteins; Neovascularization, Pathologic; Piperidines; Proto-Oncogene Proteins c-akt; Pyridines; Vascular Endothelial Growth Factor A