2. Academic Validation
  3. The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy

The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy

  • Eur J Med Chem. 2018 Nov 5:159:1-9. doi: 10.1016/j.ejmech.2018.09.044.
Guochao Liao 1,  Deying Yang 2,  Leilei Ma 2,  Wenwei Li 2,  Liqin Hu 2,  Liming Zeng 2,  Peng Wu 2,  Lixin Duan 2,  Zhongqiu Liu 3
Affiliations

Affiliations

  • 1 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: [email protected].
  • 2 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 3 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: [email protected].
PMID: 30253242 DOI: 10.1016/j.ejmech.2018.09.044
Abstract

In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for Cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for Cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for Cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

Keywords

AMG-232; Cancer therapy; MDM2 inhibitors; MDM2-p53 interactions; Piperidinones.

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