CBL0137 | Inhibitor of the histone chaperone FACT

CBL0137 (1197996-80-7) 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 disassemble 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

References/Citations:

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 606 594