Uses
Curaxin-137 is an inhibitor of the histone chaperone FACT (facilitates chromatin transcription) that simultaneously suppresses NF-κB and activates p53.
Definition
ChEBI: CBL0137 is a member of the class of carbazoles that is 9H-carbazole which is substituted by acetyl groups at positions 3 and 6, and by a 2-isopropylethyl group on the nitrogen atom (position 9). It is a modulator of histone chaperone FACT (FAcilitates Chromatin Transcription) - interaction of CBL0137 with the FACT complex results in simultaneous NF-kappa beta suppression, Heat Shock Transcription Factor 1 (HSF1) suppression and p53 activation - and shows antitumour effects in animal models of various cancers. It has a role as a NF-kappaB inhibitor, a p53 activator, an antineoplastic agent and an apoptosis inducer. It is a member of carbazoles, a secondary amino compound, a tertiary amino compound, an aromatic ketone and a methyl ketone.
Biological Activity
ec50: 0.37 μm for activating p53; 0.47 μm for inhibiting nf-κbcbl0137 is a curaxin that activates p53 and inhibits nf-κb.the p53 and nuclear factor κb (nf-κb) pathways are dysregulated in almost all tumors, making them attractive targets for therapeutic activation and inhibition, respectively.
in vitro
cbl0137 was identified as a metabolically stable curaxin activating p53 and inhibiting nf-κb. cbl0137 could functionally inactivate chromatin transcription complex, resulting in the effects on p53 and nf-κb and promoting cancer cell death [1]. it was also found that cbl0137 alone was a potent inducer of apoptosis in pancreatic cancer cell lines and was toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells [2].
in vivo
in mice, cbl0137 was effective against orthotopic gemcitabine resistant panc-1 model and patient derived xenografts, in which cbl0137 anti-tumor effect related with overexpression of fact. moreover, the combination effects of cbl0137 and gemcitabine might be explained by the ability of cbl0137 to inhibit several transcriptional programs induced by gemcitabine, including nf-kappab response and expression of ribonucleotide reductase [2].
References
1. a. v. gasparian, c. a. burkhart, a. a. purmal, et al. curaxins: anticancer compounds that simultaneously suppress nf-κb and activate p53 by targeting fact. sci.transl.med. 3(95), (2011).2. c. burkhart, d. fleyshman, r. kohrn, et al. curaxin cbl0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer. oncotarget 5(22), 11038-11053 (2014).
