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<p>The p53–MDM2/MDMX interaction represents a pivotal therapeutic target in oncology, with the cis-imidazoline scaffold of Nutlin-3a serving as the first nanomolar small-molecule MDM2 antagonist. This comprehensive review traces the evolution of Nutlin derivatives from lead optimization to clinical translation. The structural modification section discusses rational strategies to enhance metabolic stability, solubility, and dual MDM2/MDMX inhibition, including the development of covalent inhibitors and PROTACs for targeted MDM2 degradation. The synthetic section details various synthetic approaches to Nutlins, integrating vicinal diamine formation, imidazoline ring construction, N-functionalization, and the nitro-Mannich reaction. Pharmacokinetic and pharmacodynamic profiling is explored, covering molecular target engagement and systemic distribution. The role of p53 status in specifying therapeutic efficacy is emphasized, along with discussion of synergistic combinations with over 60 agents. Preclinical proof-of-concept is presented across solid and hematological malignancies, with clinical validation in MDM2-amplified cancers and emerging evidence for non-oncological applications.</p><p></p>

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The evolution of Nutlins as p53-MDM2 inhibitors

  • 期刊论文

  • 发表日期：

    2025年11月5日

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  • Daniil R. Bazanov,
  • Natalia A. Lozinskaya

摘要

The p53–MDM2/MDMX interaction represents a pivotal therapeutic target in oncology, with the cis-imidazoline scaffold of Nutlin-3a serving as the first nanomolar small-molecule MDM2 antagonist. This comprehensive review traces the evolution of Nutlin derivatives from lead optimization to clinical translation. The structural modification section discusses rational strategies to enhance metabolic stability, solubility, and dual MDM2/MDMX inhibition, including the development of covalent inhibitors and PROTACs for targeted MDM2 degradation. The synthetic section details various synthetic approaches to Nutlins, integrating vicinal diamine formation, imidazoline ring construction, N-functionalization, and the nitro-Mannich reaction. Pharmacokinetic and pharmacodynamic profiling is explored, covering molecular target engagement and systemic distribution. The role of p53 status in specifying therapeutic efficacy is emphasized, along with discussion of synergistic combinations with over 60 agents. Preclinical proof-of-concept is presented across solid and hematological malignancies, with clinical validation in MDM2-amplified cancers and emerging evidence for non-oncological applications.