Curaxins: Anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT

Alexander V. Gasparian, Catherine A. Burkhart, Andrei A. Purmal, Leonid Brodsky, Mahadeb Pal, Madhi Saranadasa, Dmitry A. Bosykh, Mairead Commane, Olga A. Guryanova, Srabani Pal, Alfiya Safina, Sergey Sviridov, Igor E. Koman, Jean Veith, Anton A. Komar, Andrei V. Gudkov, Katerina V. Gurova

Research output: Contribution to journalArticlepeer-review

Abstract

Effective eradication of cancer requires treatment directed against multiple targets. The p53 and nuclear factor κB (NF-κB) pathways are dysregulated in nearly all tumors, making them attractive targets for therapeutic activation and inhibition, respectively. We have isolated and structurally optimized small molecules, curaxins, that simultaneously activate p53 and inhibit NF-κB without causing detectable genotoxicity. Curaxins demonstrated anticancer activity against all tested human tumor xenografts grown in mice. We report here that the effects of curaxins on p53 and NF-κB, as well as their toxicity to cancer cells, result from "chromatin trapping" of the FACT (facilitates chromatin transcription) complex. This FACT inaccessibility leads to phosphorylation of the p53 Ser392 by casein kinase 2 and inhibition of NF-κB-dependent transcription, which requires FACT activity at the elongation stage. These results identify FACT as a prospective anticancer target enabling simultaneous modulation of several pathways frequently dysregulated in cancer without induction of DNA damage. Curaxins have the potential to be developed into effective and safe anticancer drugs.

Original languageEnglish
Article number95ra74
JournalScience Translational Medicine
Volume3
Issue number95
DOIs
StatePublished - 10 Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Medicine (all)

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