title: Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT.
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 Ser(392) 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.
authors.affiliation: Cleveland BioLabs Inc., Buffalo, NY 14203, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gasparian
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Burkhart
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Purmal
authors.forename: Leonid
authors.initials: L
authors.lastname: Brodsky
authors.forename: Mahadeb
authors.initials: M
authors.lastname: Pal
authors.forename: Madhi
authors.initials: M
authors.lastname: Saranadasa
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Bosykh
authors.forename: Mairead
authors.initials: M
authors.lastname: Commane
authors.forename: Olga A
authors.initials: OA
authors.lastname: Guryanova
authors.forename: Srabani
authors.initials: S
authors.lastname: Pal
authors.forename: Alfiya
authors.initials: A
authors.lastname: Safina
authors.forename: Sergey
authors.initials: S
authors.lastname: Sviridov
authors.forename: Igor E
authors.initials: IE
authors.lastname: Koman
authors.forename: Jean
authors.initials: J
authors.lastname: Veith
authors.forename: Anton A
authors.initials: AA
authors.lastname: Komar
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Katerina V
authors.initials: KV
authors.lastname: Gurova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D047390:Casein Kinase II / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D035602:Transcriptional Elongation Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000600493:CBLC137; D002227:Carbazoles; D002843:Chromatin; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D016328:NF-kappa B; C073537:SSRP1 protein, human; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D002945:Cisplatin