Ligand-based optimization and biological evaluation of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide derivatives as potent intrinsically disordered protein c-Myc inhibitors.

Abstract The transcription factor c-Myc is a well-known onco-protein and an intrinsically disordered protein (IDP). As its aberrant expression is frequently observed in various human cancers, c-Myc is considered as a key drug target. However, due to its high conformational flexibility, directly targeting c-Myc remains difficult. Here we explored the structure–activity relationships (SAR) of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide compounds and reported sixteen novel active compounds. Among them, compound PKUMDL-CLM-32 (hereafter, 32) showed the best anti-proliferation activity in cells with an EC50 of 3.3 μM. We demonstrated that 32 directly disrupts c-Myc/Max interaction and induces the degradation of c-Myc protein in cells. We showed that 32 induces cell cycle arrest at S phase and promotes apoptosis of HL-60 cells. This study provides an example of using ligand-based analysis to optimize IDP ligands.