Work

Disruption of c-Myc/Max heterodimerization induced by a novel anticancer agent endowed with 1,3-diphenylurea moiety: an in silico, chemoproteomics-based, and in vitro combined approach

Year: 2025

Type: article

Abstract: The intrinsically disordered protein (IDP) c-Myc plays a crucial role in regulating cell growth, proliferation, and apoptosis, making it a significant target in cancer therapy. Herein, we report an integrated approach combining computational and biological methods to uncover key c-Myc structural aspects. A virtual screening campaign considering commercially available libraries was performed, leading to the selection of 11 promising c-Myc binders. Preliminary biophysical and biological analysis, including Surface Plasmon Resonance (SPR) and MTT [(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)] assays, highlighted three new potential c-Myc/Max heterodimerization inhibitors. Among them, 11 emerged as the most active one, displaying promising K D values on c-Myc (~60 μM), only slightly higher than the known binder 10058-F4 (with a dissociation constant (K D ) ~40 μM) and on Max (with a K D ~ 80 μM). Notably, 11 showed significant antiproliferative effects on three different cancer cell lines (i.e., leukemia, colorectal cancers) in a dose- and cell-dependent manner. Importantly, a significant decrease in c-Myc levels was observed, especially in U937 leukemia cells with an 85 % reduction. Finally, molecular dynamics simulations and proteomic studies further identified its binding site and key interacting residues. Summarizing, this work provides a solid research strategy and valuable insights for the identification of new c-Myc/Max disruptors.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.146187