Yang, Y. 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: 23.89). 07/2005; 7(6):547-59. DOI: 10.1016/j.ccr.2005.04.029
Source: PubMed

ABSTRACT 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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    • "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 · 5.40 Impact Factor
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    • "Accordingly, smallmolecule MDM2 inhibitors have been developed that specifically target the E3 ligase activity of MDM2 (Yang et al, 2005). HLI98 represents a small-molecule MDM2 inhibitor of the first generation that blocks the E3 ligase activity of MDM2 leading to stabilization of p53, p53-dependent transcription and induction of cell death (Di et al, 2011; Yang et al, 2005). A structural study confirmed the mode of action of small-molecule MDM2 antagonists nutlins showing that these compounds bind MDM2 via the p53-binding pocket, thereby preventing its interaction with p53 (Vassilev et al, 2004). "
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    ABSTRACT: Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions.
    EMBO Molecular Medicine 07/2012; 4(7):545-56. DOI:10.1002/emmm.201100707 · 8.25 Impact Factor
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    • "All these data suggest that the observed effects of HBX 19,818 are likely the result of USP7 targeting. Most attempts to target Mdm2 have focused on the identification of small molecules, such as the nutlins, which prevent its interaction with p53 (Vassilev et al., 2004), or on inhibiting its E3 ligase activity (Yang et al., 2005). We adopted an alternative approach based on the identification of small-molecule inhibitors of USP7; an ubiquitin-specific protease required for Mdm2-dependent p53 destabilization. "
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    ABSTRACT: The human USP7 deubiquitinating enzyme was shown to regulate many proteins involved in the cell cycle, as well as tumor suppressors and oncogenes. Thus, USP7 offers a promising, strategic target for cancer therapy. Using biochemical assays and activity-based protein profiling in living systems, we identified small-molecule antagonists of USP7 and demonstrated USP7 inhibitor occupancy and selectivity in cancer cell lines. These compounds bind USP7 in the active site through a covalent mechanism. In cancer cells, these active-site-targeting inhibitors were shown to regulate the level of several USP7 substrates and thus recapitulated the USP7 knockdown phenotype that leads to G1 arrest in colon cancer cells. The data presented in this report provide proof of principle that USP7 inhibitors may be a valuable therapeutic for cancer. In addition, the discovery of such molecules offers interesting tools for studying deubiquitination.
    Chemistry & biology 04/2012; 19(4):467-77. DOI:10.1016/j.chembiol.2012.02.007 · 6.59 Impact Factor
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