CBL0137 hydrochloride (Curaxin-137 hydrochloride) activates p53 and inhibits NF-kB (EC50: 0.37/0.47 μM) in the cell-based p53 and NF-kB reporter assays, respectively. It also suppresses histone chaperone FACT.

NF-κB:0.47 μM(EC50), p53:0.37 μM(EC50), FACT:

In pancreatic cancer cell lines, CBL0137 is an effective inducer of apoptosis. It is toxic not only for proliferating various tumor cells, but also for pancreatic cancer stem cells. CBL0137 can activate p53 and inhibit cellular stress pathways mediated by HSF-1 and NF-κB. CBL0137 binds DNA but does not cause any sort of chemical modifications in DNA. However, CBL0137 binding to DNA leads to functional inactivation of the Facilitates Chromatin Transcription (FACT) complex. In CBL0137-treated cells, FACT is lost from the nucleoplasm and trapped in chromatin, resulting in the inhibition of FACT-dependent transcription, including NF-kB-mediated transcription. Additionally, chromatin trapping of FACT leads to casein kinase 2 (CK2)-dependent phosphorylation and activation of p53.

In mice, CBL0137 is potent against several Pancreatic ductal adenocarcinoma (PDA) models, including patient derived xenografts and orthotopic gemcitabine resistant PANC-1 model. CBL0137 targets glioblastoma (GBM) according to its proposed mechanism of action, crosses the blood-brain barrier, and is efficacious in both TMZ-responsive and -resistant orthotopic models. The property of crossing the blood-brain barrier, especially when administered i.v, bodes well for the potential of this drug to treat CNS tumors. In orthotopic models, i.v. administration leads to greater tumor tissue accumulation than oral dosing, leading to greater bioavailability.

MiaPaca2 and BxPC-3 cells are treated with CBL0137 hydrochloride for 4 or 24 h. Cells are harvested in 1× Cell Culture Lysis Reagent containing protease and phosphatase inhibitors. Lysates 5 to 20 μg are separated on SDS-PAGE gels and transferred to PVDF membranes. Blots are probed with antibodies specific for SSRP1, SPT16, RRM1, and RRM2.

Effects of CBLC137 (2 μM for 24 hours) on cell cycle in tumor (HT1080, RCC45, MiaPaca) and normal cells (Wi38, NKE-hTERT) are examined using FACS analysis of propidium iodide-stained cells.

Animal Models: xenograft mouse models of cancer. Formulation: water. Dosages: 30 mg/kg. Administration: p.o.