Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the beta-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of beta-catenin and unregulated beta-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear beta-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the beta-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APC(min) mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear beta-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APC(min) mice, confirming the impact on the beta-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene. Key messages center dot ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations. center dot ZKN-0013 promoted read through of premature stop codons in the APC gene. center dot In APC(min) mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas. center dot ZKN-0013 treatment in APC(min) mice resulted in reduced anemia and increased survival.