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EC50: 0.37 μM for activating p53; 0.47 μM for inhibiting NF-κB
CBL0137 (hydrochloride) 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].
Clinical trial: A phase 1 trial of CBL0137 in patients with metastatic or unresectable advanced solid neoplasm and a study of IV CBL0137 in previously treated hematological subjects are crrently recruiting patients [https://clinicaltrials.gov/ct2/results term=CBL0137&Search=Search].
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).
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