Targeting p53 by small molecules in hematological malignancies

Journal of Hematology & Oncology (Impact Factor: 4.81). 03/2013; 6(1):23. DOI: 10.1186/1756-8722-6-23
Source: PubMed


p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative effects of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor activities in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.

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Available from: Manujendra Saha
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    • "Since p53 is commonly inactivated in various human cancers, its ''re-activation'' represents a major therapeutic strategy. Specifically, targeting the interactions of p53 with its major negative regulators, MDM2 and MDM4, recently emerged as an important therapeutic approach, with multiple examples of both, small molecules and peptides being utilized as p53-MDM2/MDM4 inhibitors (Li and Lozano 2013; Saha et al. 2013; Wang et al. 2012; Zhao et al. 2013). p53-MDM2/MDM4 interactions are mediated primarily by three key hydrophobic residues in p53: 19 Phe, 23 Trp, and 26 Leu (Kussie et al. 1996; Pazgier et al. 2009; Popowicz et al. 2008), and similar though not identical, hydrophobic surface grooves in MDM2 and MDM4 (Zhao et al. 2013). "
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    ABSTRACT: A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53–MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S-alkylation-based stapling, point mutations increasing hydrophobicity in key residues as well as improvement of cell-permeability by introduction of polycationic sequence(s) that were woven into the sequence of parental peptide. Selected analogue, ArB14Co, was also tested in vivo and exhibited potent anticancer bioactivity at the low dose (3.0 mg/kg). Collectively, our findings suggest that application of stapling in combination with rational design of polycationic short analogues may be a suitable approach in the development of physiologically active p53–MDM2/MDMX peptide inhibitors.
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    • "General comments on MDM2/4 antagonists MDM2/4 antagonists (either low molecular weight or peptides) are likely to be of most value in cancers with WT p53 and high expression of either MDM2 or MDM4. These include pediatric malignancies such as sarcomas, leukemias, neuroblastomas and retinoblastomas [54] [55] [57], melanomas [78] and luminal-type breast cancers [8]. On the other hand, these agents are unlikely to find application in tumors with a high prevalence of p53 mutations such as triple-negative breast cancer or high grade serous ovarian cancers [8]. "
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    ABSTRACT: P53 is the most frequently mutated gene in human cancer, but until recently was believed to be “undruggable”.•P53 is particularly frequently mutated (> 80%) in difficult to treat tumors (TNBC, HGS ovarian, squamous lung cancer).•Several drugs are now available that can reactivate mutant p53 to a form exhibiting wild-type properties (eg, PRIMA1MET).•Other compounds are available that block the degradation of wild-type p53 (e.g., nutlins).•p53-targeting drugs currently undergoing clinical trials include PRIMA1MET (APR-246) and nutlin derivatives.
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    • "Because MDM2 inhibitors depend on p53 activation in cells expressing wild type p53, hematological malignancies that mostly retain wild type genotype of TP53 are potential attractive targets for MDM2 inhibitor-based therapy. Nutlin-3 has been shown to be a potent inducer of apoptosis in cell lines deriving from hematological malignancies, including MM, ALL, AML, CLL, and Hodgkin's lymphoma [57, 58]. In MM, nutlin-3 demonstrated potent antimyeloma activity in MM cell lines, primary MM patient samples, as well as in MM cells grown in the bone marrow microenvironment [58, 59]. "
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    ABSTRACT: p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma.
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