Chapter Twelve - p53–MDM2 and MDMX Antagonists

• Autores: Constantinos Neochoritis, Natalia Estrada, Kareem Khoury, Alexander Dömling
• Localización: Annual reports in medicinal chemistry, ISSN 0065-7743, Vol 49, 2014, págs. 167-187
• Idioma: inglés
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• Resumen

  • Abstract The protein–protein interaction of the oncogene mouse double minute 2 (MDM2) and the transcription factor tumor-suppressor p53 is an emerging target in oncology, and prove of concept for their druggability has been established by the discovery of Nutlin. The approach is notably different from many classical genotoxic anticancer therapeutics and can potentially add to the future arsenal of anticancer weapons. A wealth of biochemical, cell biological, and structural biological data is available, and different small molecular weight scaffolds with impressive activities have been disclosed. The structural requirements for small-molecule MDM2 antagonist are well understood, not so for the upcoming MDMX antagonists. The recent interim results of a phase I trial reported by ROCHE on a Nutlin derivative are promising. Several compounds from other companies are moving toward advanced clinical trials.