Small Molecule Inhibitors of the p53-MDM2

Hu, Chunqi; Hu, Yongzhou

doi:10.2174/092986708784872375

Cited by 34 publications

(26 citation statements)

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“…Further, downstream p53 signaling events are dependent on the disruption of the physical interaction between these two proteins [155]. Three-dimensional modeling studies of the site of p53-MDM2 interaction have enabled the consideration of small molecule strategies to disrupt this interaction and thereby activate downstream p53 signaling events [156][157][158][159][160]. Because the p53-MDM2 interaction is unique in that it has a narrow hydrophobic cleft also referred to as a ''pocket'', a small-molecule inhibitor need only occupy this pocket or cleft by mimicking p53 [159].…”

Section: Targeted Manipulation Of Cell Death Signalingmentioning

confidence: 99%

The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

et al. 2009

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The molecular subversion of cell death is acknowledged as a principal contributor to the development and progression of cancer. The p53 tumor suppressor protein is among the most commonly altered proteins in human cancer. The p53 protein mediates critical functions within cells including the response to genotoxic stress, differentiation, senescence, and cell death. Loss of p53 function can result in enhanced rates of cell proliferation, resistance to cell death stimuli, genomic instability, and metastasis. The community of cancer scientists is now in possession of a vast repository of information regarding the frequency, specific mechanisms, and clinical context of cell death deregulation in cancer. This information has enabled the design of therapeutic agents to target proteins, including p53. The feasibility and impact of targeting cell death signaling proteins has been established in preclinical models of human cancer. The appropriate application of these targeted agents is now being established in clinical trials.

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Section: Targeted Manipulation Of Cell Death Signalingmentioning

confidence: 99%

The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

et al. 2009

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“…Meanwhile, cocrystal structures and docking studies indicated that their binding mode mimicked that of p53 peptide. 28 So far, small-molecule inhibitors of MDM2 are all designed to mimic the residues Phe19, Trp23, and Leu26 in p53 and their interactions with MDM2. 20 Although the potential benefits for the inhibition of the p53−MDM2 protein−protein interaction have been recognized for nearly 20 years, there are currently still limited classes of highly potent small-molecule inhibitors that show potent antitumor efficacy.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction

et al. 2012

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The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K(i) = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K(i) = 260.0 nM) and 60a (K(i) = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.

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“…The stability of the p53-HDM2 complex is primarily due to the hydrophobic interactions involving the three cleft-binding residues, as confirmed by amino-acid substitution studies 11. This structure greatly stimulated the search for HDM2 inhibitors with chemotherapeutic activity, and much success has been achieved in this area 12,13. The best inhibitors of HDM2-p53 binding are either small molecules that are very hydrophobic or oligomeric molecules that arrange hydrophobic sidechains into the same three-dimensional arrangement as the bound p53 helix.…”

Section: Introductionmentioning

confidence: 92%

N-Acylpolyamine inhibitors of HDM2 and HDMX binding to p53

Hayashi

Wang

Hara

et al. 2009

Bioorganic & Medicinal Chemistry

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Selective inhibition of protein-protein interactions important for cellular processes could lead to the development of new therapies against disease. In the area of cancer, overexpression of the proteins human double minute 2 (HDM2) and its homolog HDMX has been linked to tumor aggressiveness. Both HDM2 and HDMX bind to p53 and prevent cell cycle arrest or apoptosis in damaged cells. Developing a strategy to simultaneously prevent the binding of both HDM2 and HDMX to p53 is an essential feature of inhibitors to restore p53 activity in a number of different cancers. Inhibition of protein-protein interactions with synthetic molecules is an emerging area of research that requires new inhibitors tailored to mimic the types of interfaces between proteins. Our strategy to create inhibitors of protein-protein interactions is to develop a non-natural scaffold that may be used as a starting point to identify important molecular components necessary for inhibition. In this study, we report an N-acylpolyamine (NAPA) scaffold that supports numerous sidechains in a compact atomic arrangement. NAPAs were constructed by a series of reductive aminations between amino acid derivatives followed by acylation at the resulting secondary amine. An optimized NAPA was able to equally inhibit the association of both HDM2 and HDMX with p53. Our results demonstrate some of the challenges associated with targeting multiple protein-protein interactions involved in overlapping cellular processes.

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Small Molecule Inhibitors of the p53-MDM2

Cited by 34 publications

References 0 publications

The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction

N-Acylpolyamine inhibitors of HDM2 and HDMX binding to p53

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