Vassilev LTp53 Activation by small molecules: application in oncology. J. Med. Chem. 48: 4491-4499

Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 08/2005; 48(14):4491-9. DOI: 10.1021/jm058174k
Source: PubMed


For Abstract see ChemInform Abstract in Full Text.

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    • "Genetic experiments in mice have demonstrated the importance of these MDM2/MDMX heterodimers in the negative regulation of p53 [65]. Owing to differences in the p53 binding sites between MDM2 and MDMX, MDM2 antagonists like Nutlin-3 have low affinity for MDMX and thus their ability to maximally inhibit p53 is diminished particularly in tumors where MDMX is over-expressed [66, 67]. This understanding has lead to the search for small molecules that inhibit MDMX as a means of activating p53 more robustly. "
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    ABSTRACT: Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.
    Full-text · Article · Apr 2014 · Apoptosis
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    • "Reactivation of p53 is critical for development of p53-targeted therapeutics [22]. It is estimated that approximately 50% of human cancers express wild type p53, and p53 is inactivated in these tumors by different mechanisms [22,23]. "
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    ABSTRACT: Focal Adhesion Kinase (FAK) is a 125 kDa non-receptor kinase that plays a major role in cancer cell survival and metastasis. We performed computer modeling of the p53 peptide containing the site of interaction with FAK, predicted the peptide structure and docked it into the three-dimensional structure of the N-terminal domain of FAK involved in the complex with p53. We screened small molecule compounds that targeted the site of the FAK-p53 interaction and identified compounds (called Roslins, or R compounds) docked in silico to this site. By different assays in isogenic HCT116p53+/+ and HCT116 p53-/- cells we identified a small molecule compound called Roslin 2 (R2) that bound FAK, disrupted the binding of FAK and p53 and decreased cancer cell viability and clonogenicity in a p53-dependent manner. In addition, dual-luciferase assays demonstrated that the R2 compound increased p53 transcriptional activity that was inhibited by FAK using p21, Mdm-2, and Bax-promoter targets. R2 also caused increased expression of p53 targets: p21, Mdm-2 and Bax proteins. Furthermore, R2 significantly decreased tumor growth, disrupted the complex of FAK and p53, and up-regulated p21 in HCT116 p53+/+ but not in HCT116 p53-/- xenografts in vivo. In addition, R2 sensitized HCT116p53+/+ cells to doxorubicin and 5-fluorouracil. Thus, disruption of the FAK and p53 interaction with a novel small molecule reactivated p53 in cancer cells in vitro and in vivo and can be effectively used for development of FAK-p53 targeted cancer therapy approaches.
    Full-text · Article · Jul 2013 · BMC Cancer
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    • "Recently, the MDM2 antagonist Nutlin-3 was reported to selectively activate Tp53 pathway, inducing cell cycle arrest of Tp53 wild type non-small cell lung cancer (NSCLC) cells, while taxol selectively killed Tp53 deficient pharyngeal squamous-cell carcinoma cells (Tokalov & Abolmaali, 2010). Moreover, modulators of Nutlin-3 might also offer a new therapeutic option for patients with tumors expressing wild type Tp53, either in mono (Vassilev, 2005) or combined therapy (Kojima et al., 2005). Inhibition of the Tp53-MDM2 interaction has been documented following nutlins administration in multiple types of cultured cells, with a high degree of specificity. "

    Full-text · Chapter · Oct 2011
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