2. Academic Validation
  3. Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4

Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4

  • Commun Chem. 2025 May 28;8(1):164. doi: 10.1038/s42004-025-01557-4.
Elena Maspero # 1,  Anna Cappa # 1,  Janine Weber 1 2,  Paolo Trifirò 1,  Raffaella Amici 1,  Agostino Bruno 1 3,  Giovanni Fagà 1 2,  Valentina Cecatiello 4 2,  Raimondo Fattori 1,  Brian Leuzzi 1,  Vincenzo Taibi 1,  Giuseppe Meroni 1 5,  Maurizio Pasi 1 6,  Alessia Romussi 1,  Luca Sartori 1,  Manuela Villa 1,  Stefania Vultaggio 1 7,  Marco Cirò 1,  Paolo Soffientini 1,  Lierin Lombardo 1,  Shakti Dahe 1,  Angela Bachi 1,  Mario Varasi 1,  Mario Rossi 8 9,  Sebastiano Pasqualato 4 2,  Ciro Mercurio 10,  Simona Polo 11 12
Affiliations

Affiliations

  • 1 IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 2 Human Technopole, Milan, Italy.
  • 3 Cor.Cor international Parma, Parma, Italy.
  • 4 Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
  • 5 Recordati S.p.A, Milan, Italy.
  • 6 Fondazione I.R.C.C.S Policlinico San Matteo, Pavia, Italy.
  • 7 Icon Pharma, Milan, Italy.
  • 8 Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Pilar, Argentina.
  • 9 Facultad de Ciencias Biomédicas, Universidad Austral, Pilar, Argentina.
  • 10 IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy. ciro.mercurio@ifom.eu.
  • 11 IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy. simona.polo@ifom.eu.
  • 12 Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy. simona.polo@ifom.eu.
  • # Contributed equally.
PMID: 40437006 DOI: 10.1038/s42004-025-01557-4
Abstract

Among the human E3 ubiquitin ligases, NEDD4 (Neural precursor cell expressed developmentally down-regulated 4) plays a critical role in development and Cancer, making it a compelling therapeutic target. However, no specific NEDD4 inhibitors have advanced in drug development. In this study, we reveal the inhibitory mechanism of Norclomipramine, a tricyclic antidepressant, which inhibits NEDD4-mediated ubiquitin chain elongation by binding to a hydrophobic pocket in the Ub exosite of the N-lobe. Building on this mechanism, we conducted a focused medicinal chemistry campaign, resulting in the development of covalent inhibitors that specifically target the non-catalytic cysteine C627. These compounds exhibit selective binding to NEDD4 over Other family members, effectively inhibiting NEDD4-mediated polyubiquitination while leaving monoubiquitinated substrates unaffected. Among these, compound 32 emerged as a potent lead (IC50 = 0.12 µM) with favorable pharmacokinetic properties, including oral bioavailability, paving the way for future in vivo efficacy studies.

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