CBL0137
FACT histone chaperone inhibitor / CBL0137 is an anticancer agent that activates p53 and suppresses NF-kB via trapping of the FACT (facilitates chromatin transcription) complex, an important histone chaperone that mediates nucleosome disassembly and reassembly and facilitates DNA transcription, replication, and repair.1,2 Importantly, it is able to intercalate DNA and disrupt DNA/histone interactions without genotoxicity. CBL0137 inhibits the self-renewal of cancer stem cells via NOTCH1 activation.3 CBL0137 downregulation of HSF1 and MYC(N) have also been demonstrated in animal models.4,5 CBL0137 has also been shown to improve immunological tumor control via facilitating release of cytokines and chemokines attracting NK, CD8+, and CD4+ T cells.6 CBL0137 was able to activate the Z-RNA sensor ZBP1 inducing necroptosis and reversing immune checkpoint blockage unresponsiveness in mouse models of melanoma.7
Biochemicals & reagents
1197996-80-7
Curaxin 137; 3,6-Diacetyl-9-(2-isopropylethyl)-9H-carbazole
1) Gasparian et al. (2011), Curaxins: anticancer compounds that simultaneously suppress NF-kB and activate p53 by targeting FACT; Sci. Transl. Med. 3 95ra74 2) Nesher et al. (2018), Role of chromatin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small molecule drugs; Cancer Res. 78 1431 3) De et al. (2018), The FACT inhibitor CBL0137 synergizes with cisplatin in small-cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells; Cancer Res.78 2396 4) Jin et al. (2018), Curaxin CBL0137 Exerts Anticancer Activity via Diverse Mechanisms; Front. Oncol. 8 598 5) Wang et al. (2020), Effective inhibition of MYC-amplified group 3 medulloblastoma by FACT-targeted curaxin drug CBL0137; Cell Death Dis. 11 1029 6) Chen et al. (2021), Stimulation of an anti-tumor immune response with “chromatin-damaging” therapy; Cancer Immunol. Immunother. 70 2073 7) Zhang et al. (2022), ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis; Nature May 25 online ahead of print
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TARGET: Transcription factor; DNA -- PATHWAY: Chromatin; Necroptosis; p53; NFkappaB; Cytokine; Notch -- RESEARCH AREA: Epigenetics; Cancer stem cells; Immunology; Cell death -- DISEASE AREA: Cancer