Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity

• DOI: 10.1016/j.bcp.2022.115184
• Publication Date: 2022-07-22T02:36:16Z
• Authors: Xiaonan Zhang; Ece Akcan; Mario Correia; Natallia Rameika; Snehangshu Kundu; Ivaylo Stoimenov; Veronica Rendo; Anna U. Eriksson; Martin Haraldsson; Daniel Globisch; Tobias Sjöblom
• Keywords: Synthetic Lethality

Loss of heterozygosity (LOH) is a hallmark feature cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported loss drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 targeted collateral lethality anticancer therapy in colorectal (CRC). Here, we report novel compound CBK034026C exhibits toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed elicited response pattern related to ATPase inhibitors. Similar ouabain, potent inhibitor the Na+/K+-ATPase, activated Nf-kB pathway. Further metabolomic profiling downregulation pathways associated antioxidant defense and mitochondrial metabolism activity, weakening protective oxidative stress induced by CBK034026C. The identification small molecule targeting caused provides avenues development agents.