Scholarlink

<p>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 (IC<sub>50</sub> = 0.12 µM) with favorable pharmacokinetic properties, including oral bioavailability, paving the way for future in vivo efficacy studies.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月28日

查看全文
  • Elena Maspero,
  • Anna Cappa,
  • Janine Weber,
  • Paolo Trifirò,
  • Raffaella Amici,
  • Agostino Bruno,
  • Giovanni Fagà,
  • Valentina Cecatiello,
  • Raimondo Fattori,
  • Brian Leuzzi,
  • Vincenzo Taibi,
  • Giuseppe Meroni,
  • Maurizio Pasi,
  • Alessia Romussi,
  • Luca Sartori,
  • Manuela Villa,
  • Stefania Vultaggio,
  • Marco Cirò,
  • Paolo Soffientini,
  • Lierin Lombardo,
  • Shakti Dahe,
  • Angela Bachi,
  • Mario Varasi,
  • Mario Rossi,
  • Sebastiano Pasqualato,
  • Ciro Mercurio,
  • Simona Polo

摘要

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.