小分子稳定非天然c-Myc多聚体利用靶向IDP的发现平台驱动降解

Intrinsically disordered proteins (IDPs) such as c-Myc remain largely undrugged despite their central role in cancer. We developed Prompt Degrader™, a computational platform that predicts transient ordered conformations in IDPs and identifies drug-like, orally bioavailable, non-covalent small molecules that stabilize degradation-prone states. Using in silico modeling of a c-Myc homodimer pocket, we identified compounds predicted to stabilize dimerization and to promote targeted protein degradation of c-Myc via a mechanism distinct from conventional PROTACs or molecular glues. Our hit RDP-02004 induced rapid, dose-dependent loss of c-Myc protein (DC₅₀ ~5-10 µM) and apoptosis across diverse MYC-dependent cancer cell lines, including multiple myeloma, lung and triple-negative breast cancer, with selectivity over non-transformed cells. RDP-02004 showed high microsomal stability and broad in vivo activity, suppressing tumor growth in three xenograft models after oral dosing. Minimal weight loss and only mild hepatic and renal findings were observed. Mechanistic studies indicated engagement of multiple protein quality-control pathways, consistent with clearance of misfolded c-Myc species. The proteasome inhibitor MG-132, the ubiquitin-activating enzyme inhibitor TAK-243, and the autophagy inhibitor Autophinib each rescued c-Myc levels after compound treatment, implicating both ubiquitin-proteasome and aggrephagy-like mechanisms. Based on these findings, we screened scaffold-divergent analogues and identified RDP-09024, which likewise showed potent c-Myc degradation and cytotoxicity with an improved off-target profile. Direct target engagement of recombinant c-Myc protein was confirmed by ligand-observed STD and WaterLOGSY NMR experiments, in which RDP-09024 showed no binding to a negative-control protein. We confirmed the predicted binding mode and pocket of RDP-09024 via hydrogen-deuterium exchange mass spectrometry (HDX-MS) with or without compound, revealing a flexible loop on c-Myc directly involved in RDP-09024 binding. Prompt Degrader™ compounds were active ex vivo in CD138⁺ multiple myeloma patient cells as well as in xenograft models and showed a significantly improved selectivity profile versus non-cancer cells. Structure-activity and pharmacophore analyses, together with structure-based design, yielded additional series with improved properties and activity (DC₅₀ < 1 µM). These data provide proof of concept that exploiting IDP conformational ensembles to stabilize degradable c-Myc assemblies can generate small-molecule c-Myc degraders and support further optimization of this platform toward safer, more selective anti-MYC therapeutics.