Enediyne Chimeras for Targeted NAMPT Degradation: Enhancing Cytotoxicity via a Radical Clock.

Based on a novel targeted protein degradation platform, Protein-Radical-Oxidation Targeting Enediyne Chimera (PROTEC), a series of chimeric enediyne compounds targeting the oncogenic protein nicotinamide phosphoribosyltransferase (NAMPT) were designed and synthesized. These compounds feature different linker lengths and cyclopropane modifications at the alkyne terminus. Computational studies showed that incorporating the cyclopropane group at the propargyl position facilitates the "radical clock" mechanism, achieving greater spatial separation and weaker orbital interactions between the two radical centers, thereby enhancing hydrogen abstraction ability. The PROTEC-4 compound exhibiting the strongest interaction with NAMPT, as demonstrated by docking studies, established significant cytotoxicity against human ovarian cancer A2780 cells with a half-inhibitory concentration (IC50) of 0.24 μM, indicating great potential for future antitumor drug development.