NEDD4 is a key E3 ubiquitin ligase involved in development and cancer, however, specific inhibitors against NEDD4 remain underdeveloped. Here, the authors identify the inhibitory mechanism of norclomipramine and develop covalent inhibitors targeting NEDD4’s non-catalytic cysteine C627, with one compound showing potent inhibition and promising pharmacokinetics, advancing therapeutic strategies against NEDD4-related diseases.
- Elena Maspero
- Anna Cappa
- Simona Polo