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c-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc-MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC50 values. L755507 successfully disrupts the c-Myc-MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix-loop-helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc-MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug.

Original publication




Journal article


J Biol Chem

Publication Date





c-Myc–MAX heterodimer, compound inhibitors, drug discovery, protein–protein interaction, virtual screening, Antineoplastic Agents, Apoptosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Binding Sites, Drug Discovery, HT29 Cells, Humans, Molecular Docking Simulation, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins c-myc, Small Molecule Libraries