Imino-tetrahydro-benzothiazole Derivatives as p53 Inhibitors:  Discovery of a Highly Potent in Vivo Inhibitor and Its Action Mechanism

Pietrancosta, Nicolas; Moumen, Anice; Dono, Rosanna; Lingor, Paul; Planchamp, Véronique; Lamballe, Fabienne; Bähr, Mathias; Kraus, Jean‐Louis; Maina, Flavio

doi:10.1021/jm060318n

Cited by 98 publications

(53 citation statements)

References 33 publications

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“…Pan-caspase inhibitor Q-VD-OPH, the Caspase-2 inhibitor ZDVAD-FMK, and the Caspase-2 colorimetric kit were all from Biovision (Mountain View, CA), whereas the in vivo active PFT␣ prodrug 22 was from Calbiochem (#506152; San Diego, CA). Primary antibodies were obtained from Abcam (Puma; Cambridge, MA), Dako (human p53; Glostrup, Denmark), Santa Cruz Biotechnology (mouse p53, p21; Santa Cruz, CA), Sigma-Aldrich (␤-actin), Millipore (␥-H2AX; Billerica, MA), Nordic Biosite (Chk1; Täby, Sweden) and Cell Signaling Technology (Caspase-9, NBS, phosphorylated (p-)NBS, p-p53, p-Chk1, Cdc2 and p-Cdc2; Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine

Höglund

Nilsson

Forshell

et al. 2009

Blood

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Introduction c-Myc is encoded by the founding member of the MYC family of oncogenic transcription factors that also includes MYCN and MYCL. Overexpression of one of these oncogenes is seen in most human cancers and represents the most frequently deregulated genetic event in cancer. The reason for the recurrent selection for Myc activation in cancer is its biologic activities, which include many of the hallmarks of cancer such as stimulation of cell proliferation, inhibition of anti-growth signals and differentiation, induction of angiogenesis and even immortalization. Paradoxically though, Myc also triggers apoptosis, 1,2 which is a cellular defense against cancer. For that reason, mutations in genes governing or executing apoptotic pathways are always accompanying Myc mutations in tumors. 3 The tumor suppressor p53 is crucial in the defense against activated Myc oncogenes and it can be activated in 2 major ways: one pathway involving the Arf tumor suppressor and one involving the upstream kinases of the DNA damage response (DDR), ATM/ATR and DNA-PK. How Myc induces Arf 4 is not completely understood, but when it does, Arf inhibits the E3 ubiquitin ligase Mdm2, which is a transcriptional target of p53 and acts as its negative regulator. 5 By inhibiting Mdm2, Arf causes p53 accumulation, resulting in the activation of genes downstream of p53, such as those encoding the cell-cycle inhibitor p21, DNA repair proteins, or proapoptotic proteins of the Bcl-2 family, like Noxa and Puma. 5 A similar scenario is the end result of Myc activating a DDR, where unscheduled Myc-induced replication causes strand breaks leading to activation of ATM, ATR or DNA-PK. 6 Downstream of these are the Chk1/2 kinases, which regulate the phosphorylation of cyclin: Cdk complexes to transiently arrest cells in the S and G2 phases of the cell cycle. They also phosphorylate p53, which disrupts the interaction with Mdm2, resulting in p53 activation and a more prolonged arrest. 7 Importantly, however, because high levels of Myc can repress p21 gene transcription, 8,9 the outcome of p53 activation by both the Arf and the DDR pathways, in the context of Myc overexpression, tips the balance toward apoptosis rather than cell-cycle inhibition. 8,10 This may explain why oncogene-induced senescence seen in many precancerous lesions is rarely seen in Myc-induced tumors, but may be triggered when Myc itself is inactivated. 11 Genetic studies in mice have shown that the pathways triggering p53 described above are essential for keeping Myc in check but they are not mutually exclusive. For instance, inactivation of Arf or Atm in Myc-transgenic mice that normally develop B-cell lymphoma (eg, E-Myc mice) results in a dramatic acceleration of disease, but inactivation of p53 is even more deleterious, suggesting that both Arf and DDR pathways are important. [12][13][14][15] Interestingly, analyses of B-cell lymphomas that develop in Myctransgenic mice and in the human disease Burkitt lymphoma (BL), where Myc is overexpressed in B lymphocytes because of translo...

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Section: Methodsmentioning

confidence: 99%

Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine

Höglund

Nilsson

Forshell

et al. 2009

Blood

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“…Since its discovery in 1999, PFTa, as well as PFTb and several more potent structural analogs of these compounds (Zhu et al 2002;Pietrancosta et al 2005;Pietrancosta et al 2006), has been widely used as a tool to assess possible therapeutic applications of p53 inhibitors in animal models. In addition to studies on prevention of toxicity associated with radioand chemotherapy (discussed earlier and reviewed in (Gudkov and Komarova 2005)), such studies have been performed in a variety of animal models mimicking different acute stresses that involve induction of p53-dependent apoptosis (e.g., ischemic heart, brain, and kidney injury) (Crumrine et al 1994;Li et al 1994;Li et al 1997;Watanabe et al 1999) or human disorders in which p53-associated apoptosis is suspected as a mechanism of cell loss (e.g., Alzheimer's and Parkinson's diseases) (Mattson et al 1993;de la Monte et al 1998;Jenner and Olanow 1998).…”

Section: Potential Applications Of P53 Inhibitorsmentioning

confidence: 99%

Pathologies Associated with the p53 Response

Gudkov¹,

Komarova²

2010

Cold Spring Harbor Perspectives in Biology

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“…34,36 Thus, p53 activation represents an important potential therapeutic target in the 5qϪ syndrome, and several p53 inhibitors are available including pifithrin. 61 However, this will be a therapeutic option in humans only if this intervention does not abrogate the critical tumor suppressor function of p53.…”

Section: P53-dependent Disease Mechanismmentioning

confidence: 99%

Advances in the 5q− syndrome

Boultwood

Pellagatti

McKenzie

et al. 2010

Blood

110

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The 5q؊ syndrome is the most distinct of all the myelodysplastic syndromes with a clear genotype/phenotype relationship. The significant progress made during recent years has been based on the determination of the commonly deleted region and the demonstration of haploinsufficiency for the ribosomal gene RPS14. The functional screening of all the genes in the commonly deleted region determined that RPS14 haploinsufficiency is the probable cause of the erythroid defect in the 5q؊ syndrome. A mouse model of the human 5q؊ syndrome has now been created by chromosomal engineering involving a large-scale deletion of the Cd74-Nid67 interval (containing RPS14). A variety of lines of evidence support the model of ribosomal deficiency causing p53 activation and defective erythropoiesis, including most notably the crossing of the "5q؊ mice" with p53-deficient mice, thereby ameliorating the erythroid progenitor defect. Emerging evidence supports the notion that the p53 activation observed in the mouse model may also apply to the human 5q؊ syndrome. Other mouse modeling data suggest that haploinsufficiency of the microRNA genes miR-145 and miR-146a may contribute to the thrombocytosis seen in the 5q؊ syndrome. Lenalidomide has become an established therapy for the 5q؊ syndrome, although its precise mode of action remains uncertain. (Blood. 2010;116(26): 5803-5811) IntroductionThe 5qϪ syndrome was first described by Van den Berghe et al in 1974. 1 The well-known clinical features of the 5qϪ syndrome described in the first report are macrocytosis, anemia, a normal or high platelet count, and hypolobulated megakaryocytes in the bone marrow. Over the years, a female preponderance and a good prognosis with approximately 10% of patients transforming to acute myeloid leukemia (AML) have been well documented. [2][3][4][5] The World Health Organization classification of myelodysplastic syndromes (MDSs) recognizes the 5qϪ syndrome as a distinct entity defined by a medullary blast count of less than 5% and the deletion of 5q [del(5q)] as the sole karyotypic abnormality. 6 It should be noted that patients not correctly defined as 5qϪ syndrome (ie, with either additional karyotypic abnormalities or excess blasts) do not have a good prognosis. 7 The majority of patients with the 5qϪ syndrome become transfusion dependent over time with the potential for iron loading. 5,8 A recent paper by Patnaik et al 2 determined that age, transfusion need at diagnosis, and dysgranulopoiesis were independent predictors of shortened survival in patients with the 5qϪ syndrome tightly defined according to World Health Organization criteria.One of the features that first stimulated research on the 5qϪ syndrome was the localization of many genes relevant to hematopoiesis to the long arm of chromosome 5 (5q). 4 The gene cluster at 5q31 includes interleukins 3, 4, 5, 9, 13, and 17␤ and granulocytemonocyte colony stimulating factor. 9 Several cytokine receptor genes are located on 5q, including colony-stimulating factor 1 receptor and platelet-derived growth fa...

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Imino-tetrahydro-benzothiazole Derivatives as p53 Inhibitors: Discovery of a Highly Potent in Vivo Inhibitor and Its Action Mechanism

Cited by 98 publications

References 33 publications

Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine

Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine

Pathologies Associated with the p53 Response

Advances in the 5q− syndrome

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