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Review
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Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges

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Review

Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges

Shaomeng Wang et al. Cold Spring Harb Perspect Med.

Abstract

MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 small-molecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.

Figures

Figure 1.
Figure 1.
Autoregulatory loop of p53 and MDM2. Activation of p53 transcribes MDM2 mRNA and increases MDM2 protein, which in turn inhibits p53 activity by three mechanisms.
Figure 2.
Figure 2.
Cocrystal structures. (A) Cocrystal structure of MDM2 (surface rendering) in complex with p53 (stick model). p53 protein uses primarily three key residues (Phe19, Trp23, and Leu26) to interact with a well-defined, surface hydrophobic pocket in MDM2. (B) Superposition of the cocrystal structures of nutlin-2/MDM2 complex and p53/MDM2 complex (PDBIDs: 1YCR and 4HG7). Nutlin-2 is shown by yellow sticks and the three key p53-binding residues are shown by green sticks with the MDM2 protein shown in the surface rendering.
Figure 3.
Figure 3.
Chemical structures of representative MDM2 inhibitors.

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