TY - JOUR T1 - Novel c-Myc–Targeting Compound <em>N</em>, <em>N</em>-Bis (5-Ethyl-2-Hydroxybenzyl) Methylamine for Mediated c-Myc Ubiquitin-Proteasomal Degradation in Lung Cancer Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 130 LP - 142 DO - 10.1124/mol.120.119719 VL - 98 IS - 2 AU - Nicharat Sriratanasak AU - Korrakod Petsri AU - Apirat Laobuthee AU - Worawat Wattanathana AU - Chanida Vinayanuwattikun AU - Sudjit Luanpitpong AU - Pithi Chanvorachote Y1 - 2020/08/01 UR - http://molpharm.aspetjournals.org/content/98/2/130.abstract N2 - Aberrant cellular Myc (c-Myc) is a common feature in the majority of human cancers and has been linked to oncogenic malignancies. Here, we developed a novel c-Myc–targeting 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 toward various human lung cancer cell lines, as well as chemotherapeutic-resistant patient-derived lung cancer cells, through apoptosis induction in comparison with chemotherapeutic drugs. The IC50 of EMD against lung cancer cells was approximately 60 µM. Mechanistically, EMD eliminated c-Myc in the cells and initiated caspase-dependent apoptosis cascade. Cycloheximide chase assay revealed that EMD tended to shorten the half-life of c-Myc by approximately half. The cotreatment of EMD with the 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 and promoted protein degradation. c-Myc inhibition and apoptosis induction were additionally shown in hematologic malignant K562 cells, indicating the generality of the observed EMD effects. Altogether, we identified EMD as a novel potent compound targeting oncogenic c-Myc that may offer new opportunities for lung cancer treatment.SIGNIFICANCE STATEMENT The deregulation of c-Myc is frequently associated with cancer progression. This study examined the effect of a new compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (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 a ubiquitin-proteasomal mechanism. The promising anticancer and c-Myc–targeted activities of EMD support its use in potential new approaches to treat c-Myc–driven cancer. ER -