TY - JOUR T1 - A novel c-myc targeting compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine, mediates c-Myc ubiquitin-proteasomal degradation in lung cancer cells. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.120.119719 SP - mol.120.119719 AU - Nicharat Sriratanasak AU - Korrakod Petsri AU - Apirat Laobuthee AU - Worawat Wattanathana AU - Chanida Vinayanuwattikun AU - Sudjit Luanpitpong AU - Pithi Chanvorachote Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/06/02/mol.120.119719.abstract N2 - Aberrant c-Myc is a common feature in the majority of human cancers and has been linked to oncogenic malignancies. As a profound activator of aggressive lung cancer, targeting c-Myc would lead to the better clinical outcome. Here we develop a novel c-Myc targeted compound N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD) and present evidence demonstrating its effectiveness in targeting c-Myc for degradation in human lung carcinoma. EMD exhibited strong cytotoxicity towards various human lung cancer cell lines ae well as chemotherapeutic-resistant patient-derived lung cancer cells through apoptosis induction, in comparison to chemotherapeutic drugs. Mechanistically, EMD eliminates c-Myc in the cells and initiates caspase-dependent apoptosis cascade. Cycloheximide chase assay revealed that EMD significantly shortened c-Myc half-life by approximately two-fold. Cotreatment of EMD with proteasome inhibitor MG132 reversed its c-Myc targeting effect, suggesting the involvement of ubiquitin-mediated proteasomal degradation in the process. We further verified that EMD strongly induced the ubiquitination of c-Myc that prompted it for protein degradation. c-Myc inhibition and apoptosis induction were additionally shown in hematologic malignant K562, indicating the generality of the observed EMD effects. Altogether, we have identified EMD as a novel potent compound targeting oncogenic c-Myc, which may offer new opportunities for lung cancer treatment.SIGNIFICANCE STATEMENT Deregulation of c-Myc is frequently associated with cancer progression. This study examined the effect of a new compound EMD in targeting c-Myc in several lung cancer cell lines and drug-resistant primary lung cancer cells. EMD induced dramatic c-Myc degradation through ubiquitin-proteasomal mechanism. The promising anti-cancer and c-Myc targeted activities of EMD support its potential new approaches to treat c-Myc driven cancer. ER -