Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV et al.. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7: 547-559

Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, 1050 Boyles Street, Frederick, MD 21702, USA.
Cancer Cell (Impact Factor: 23.52). 07/2005; 7(6):547-59. DOI: 10.1016/j.ccr.2005.04.029
Source: PubMed


The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis, although other p53-independent toxicity was also observed.

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    • "Considerable evidence reveals that disruption of p53-MDM2 interaction can lead to accumulation of p53 and restoration of its tumor-suppressive function [9,10]. Both rHSA-P53i and rHSA-PMI were designed to elicit inhibitory activity against MDM2 and its homolog, MDMX [8,32]. "
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    ABSTRACT: Therapeutic peptides offer a high degree of specificity, potency, and low toxicity; making them promising candidates for cancer therapy. Despite these advantages, a number of hurdles, such as poor serum stability and inefficient cellular penetration, must be overcome. Fusing a therapeutic peptide to human serum albumin (HSA) is a common approach to extend the serum stability of a peptide that binds to extracellular receptors. However, no study has shown that this approach can be applied to target intracellular proteins. Here we demonstrate the feasibility of using a recombinant human serum albumin (rHSA) fusion protein to simultaneously deliver two types of molecules: a peptide capable of binding an intracellular target, as well as fatty acid (FA)-modified FITC (FA-FITC). Two peptides reported to disrupt the intracellular p53 and MDM2/MDMX interaction were fused to the C-terminal of HSA. Cellular and biochemical studies indicate that rHSA fusion proteins were efficiently taken up by SJSA-1 cells and retained MDM2- and MDMX-binding activity. By inducing the accumulation of p53, both fusion proteins promoted efficient cytotoxicity in SJSA-1 cells via caspase activation. Long chain fatty acid (LCFA) transportation is an essential endogenous function of HSA. This study also demonstrates that rHSA fusion proteins formed highly stable complexes with FA-FITC via non-covalent interactions. FA-FITC complexed with HSA could be internalized efficiently and rHSA-P53i and rHSA-PMI retained apoptotic activity as complex components. It is expected that such an approach can ultimately be used to facilitate intracellular delivery of two anticancer therapeutics, each with distinct but complimentary mechanisms, to achieve synergistic efficacy.
    PLoS ONE 11/2013; 8(11):e80926. DOI:10.1371/journal.pone.0080926 · 3.23 Impact Factor
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    • "A complementary approach to prevent p53 degradation by MDM2 is to develop agents designed to inhibit the E3 ligase activity of MDM2 directly so as to mimic the effects of ARF or the ribosomal protein L11. Recently, small-molecule inhibitors have been identified that specifically target the E3 ligase activity of MDM2[146]. The efficacy and molecular effects of these inhibitors on the biochemical functions of p53 still remain to be defined. "
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    ABSTRACT: The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
    07/2013; 27(4):254-71. DOI:10.7555/JBR.27.20130030
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    • "On account of the importance of the p53-MDM2/ MDMX pathway in the initiation and development of wild-type p53- containing tumors, intensive studies over the past decade have been aiming to identify small molecules that could specifically target individual protein molecules of this pathway for developing a better moleculetargeting anticancer therapy [25]. Several small molecules or peptides have been reported to activate p53 by either blocking its binding to MDM2 [26] [27] [28], inhibiting MDM2 E3 ubiquitin ligase activity [29], or inhibiting MDMX-p53 binding [30]. Activating p53 by targeting its deacetylase(s) is another new strategy. "
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    ABSTRACT: Toxicity and chemoresistance are two major issues to hamper the success of current standard tumor chemotherapy. Combined therapy of agents with different mechanisms of action is a feasible and effective means to minimize the side effects and avoid the resistance to chemotherapeutic drugs while improving the antitumor effects. As the most essential tumor suppressor, p53 or its pathway has been an attractive target to develop a new type of molecule-targeting anticancer therapy. Recently, we identified a small molecule, Inauhzin (INZ), which can specifically activate p53 by inducing its deacetylation. In this study, we tested if combination with INZ could sensitize tumor cells to the current chemotherapeutic drugs, cisplatin (CIS) and doxorubicin (DOX). We found that compared with any single treatment, combination of lower doses of INZ and CIS or DOX significantly promoted apoptosis and cell growth inhibition in human non-small lung cancer and colon cancer cell lines in a p53-dependent fashion. This cooperative effect between INZ and CIS on tumor suppression was also confirmed in a xenograft tumor model. Therefore, this study suggests that specifically targeting the p53 pathway could enhance the sensitivity of cancer cells to chemotherapeutic agents and markedly reduce the doses of the chemotherapy, possibly decreasing its adverse side effects.
    Neoplasia (New York, N.Y.) 05/2013; 15(5):523-34. DOI:10.1593/neo.13142 · 4.25 Impact Factor
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