[CAS NO. 1197397-89-9] CBL0137 HCl

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PRODUCTS SPECIFICATIONS [1197397-89-9]

Catalog

SLK-S8483

Brand

Selleck

CAS

1197397-89-9

DESCRIPTION [1197397-89-9]

Overview

MDL	MFCD28160457
Molecular Weight	372.89
Molecular Formula	C21H24N2O2.HCl
SMILES	CC(NCCN1C2=C(C3=C1C=CC(C(C)=O)=C3)C=C(C(C)=O)C=C2)C.[H]Cl

For research use only.

Storage

3 years,-20°C,powder
1 years,-80°C,in solvent

Shipping

Room temperature shipping(Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Concentration Volume Mass	1 mg	5 mg	10 mg
1 mM	2.6818 mL	13.4088 mL	26.8176 mL
5 mM	0.5364 mL	2.6818 mL	5.3635 mL
10 mM	0.2682 mL	1.3409 mL	2.6818 mL
50 mM	0.0536 mL	0.2682 mL	0.5364 mL

Description

CBL0137 (CBLC137, Curaxin 137) HCl activates and inhibits with EC50s of 0.37 μM and 0.47 μM in the cell-based p53 and NF-kB reporter assays, respectively. It also inhibits histone chaperone (facilitates chromatin transcription complex).

Targets

FACT ^[1]	p53 ^[1] (Cell-free assay)	NF-κB ^[1] (Cell-free assay)
	0.37 μM(EC50)	0.47 μM(EC50)

In vitro

CBL0137 is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. CBL0137 and related molecules can simultaneously activate p53 and inhibit cellular stress pathways mediated by NF-κB and HSF-1. CBL0137 binds DNA but does not cause any sort of chemical modifications in DNA and therefore lacks genotoxicity. However, CBL0137 binding to DNA leads to functional inactivation of the Facilitates Chromatin Transcription (FACT) complex, a chromatin remodeling complex involved in transcription, replication, and DNA repair. 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 vivo

In mice, CBL0137 is effective against several Pancreatic ductal adenocarcinoma (PDA) models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. 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. Normal brain tissue accumulation of CBL0137 does not cause observable neurotoxicity.

References

[1] Gasparian AV, et al. Sci Transl Med. 2011, 3(95):95ra74.
[2] Burkhart C, et al. Oncotarget. 2014, 5(22):11038-53.
[3] Barone TA, et al. Neuro Oncol. 2017,19(2):186-196.