CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity

Tanner, Stefan; Barberis, Alcide

doi:10.1186/1477-5751-3-5

Cited by 27 publications

(20 citation statements)

References 27 publications

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“…Recently, pharmacogenomic approaches have also been proposed, with the use of synthetic compounds able to bind specifically to the DBD of the p53 mutants and to restore their proper protein configuration, and, thus, allow DNA binding (Bykov et al 2002, Tanner & Barberis 2004). These small synthetic compounds could be used in combination with traditional chemotherapy to sensitize poorly differentiated thyroid cancer cells to the cytotoxic effect of these agents.…”

Section: Possible Role Of P53 Family Proteins In Gene Therapymentioning

confidence: 99%

p53 family proteins in thyroid cancer

Malaguarnera¹,

Vella²,

Vigneri³

et al. 2007

Endocr Relat Cancer

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At variance with other human malignancies, p53 mutations are not frequent in thyroid cancer and are believed to be responsible mainly for cancer progression to poorly differentiated and aggressive phenotype. p63 and p73, two proteins with a high degree of homology with p53, are overexpressed in thyroid cancer, but their role in cancer initiation or progression is controversial. Regulation of p53 family protein function depends on: (1) the balance between the expression of transcriptionally active (p53, TAp63, and TAp73) and inactive isoforms (DNp63 and DNp73); (2) their interaction and competition at DNA-responsive elements; (3) their interaction with regulatory proteins, either inhibitory or activating. In thyroid cancer, therefore, although mutations of the p53 oncosuppressor protein family are rare, other mechanisms are present, including aberrant expression of p53 family dominant negative isoforms, up-regulation of inhibitory proteins, and functional inhibition of activating proteins. The overall result is a defective oncosuppressor activity. These inactivating mechanisms may be present in the early stages of thyroid cancer and in different cancer histotypes. A better understanding of this complex network may not only ameliorate our comprehension of cancer biology, but also open the possibility of innovative diagnostic procedures and the development of targeted therapies.

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Section: Possible Role Of P53 Family Proteins In Gene Therapymentioning

confidence: 99%

p53 family proteins in thyroid cancer

Malaguarnera¹,

Vella²,

Vigneri³

et al. 2007

Endocr Relat Cancer

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show abstract

“…Those molecules are targeted against wild-type p53 core domain and should bind generically to most mutants. Other molecules have been proposed to stabilize the folded state of the core domain of p53 [e.g., CP-31398 (12)], but, unlike the aforementioned examples, do not bind reversibly to the core domain (10,13,14) and promote anticancer effects in vivo via routes other than thermal stabilization of p53 (15).…”

mentioning

confidence: 99%

Targeted rescue of a destabilized mutant of p53 by an in silico screened drug

Boeckler

Joerger²,

Jaggi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

337

310

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The tumor suppressor p53 is mutationally inactivated in Ϸ50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in Ϸ75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in silico analysis of the crystal structure using virtual screening and rational drug design. One of them, a carbazole derivative (PhiKan083), binds to the cavity with a dissociation constant of Ϸ150 M. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the proteinPhiKan083 complex at 1.5-Å resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimization. The Y220C mutant is an excellent ''druggable'' target for developing and testing novel anticancer drugs based on protein stabilization. We point out some general principles in relationships between binding constants, raising of melting temperatures, and increase of protein half-lives by stabilizing ligands.NMR screen ͉ oncogenic mutant ͉ protein stabilization ͉ virtual drug design ͉ crystal structure

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“…Cancer 41 We hypothesized that intercalation of DNA by acridine derivatives may activate a unique p53 response, which is different from DNA damage induced by ionizing radiation, UV light exposure, or DNA-damaging agents. Activation of p53 led to cell death in acridine drug-exposed cells.…”

mentioning

confidence: 99%

Acridine derivatives activate p53 and induce tumor cell death through bax

Wang

Ho²,

Dicker³

et al. 2005

Cancer Biology & Therapy

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CP-31398 activates wild-type p53 by a novel mechanism that does not involve phosphorylation of the amino-terminus of p53 and disassociation of MDM2. To identify more potent CP-31398-like p53 activators, we synthesized 4 acridine derivatives with a similar structure to CP-31398. These four compounds induced strong p53 transcription in cells with wild-type p53. We also found that several randomly chosen acridine derivatives, including 9-aminoacridine, amsacrine, quinacrine and acridine orange, induced p53 transcriptional activity. All these acridine derivatives stabilized p53 protein by blocking its ubiquitination, without phosphorylation of ser15 or ser20 on p53. Furthermore, acridine derivatives induced p53-dependent cell death. Knockout of Bax, a p53 target and a key cell death inducer in both intrinsic and extrinsic apoptotic pathways, blocked acridine derivatives from inducing cell death. In addition, in vivo delivery of quinacrine and amsacrine induced p53 transcriptional activity in tumor xenografts. Our results reveal that DNA-intercalating acridine derivatives can induce p53 stabilization by a manner similar to CP-31398. These findings provide insights into p53 regulation in response to DNA intercalating drugs and may assist new anti-cancer drug design.

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CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity

Cited by 27 publications

References 27 publications

p53 family proteins in thyroid cancer

p53 family proteins in thyroid cancer

Targeted rescue of a destabilized mutant of p53 by an in silico screened drug

Acridine derivatives activate p53 and induce tumor cell death through bax

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