Curaxin-137 | CBL0137 | CAS#1197996-80-7 | FACT inhibitor

MedKoo Cat#: 206703 | Name: CBL0137

Description:

WARNING: This product is for research use only, not for human or veterinary use.

CBL0137, also known as Curaxin 137 or CBLC137, is a metabolically stable curaxin that activates p53 with an EC50 value of 0.37 µM and inhibits NF-κB with an EC50 of 0.47 µM. CBL0137 inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma. CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer.

Chemical Structure

CBL0137

CAS#1197996-80-7 (free base)

Theoretical Analysis

MedKoo Cat#: 206703

Name: CBL0137

CAS#: 1197996-80-7 (free base)

Chemical Formula: C21H24N2O2

Exact Mass: 336.1838

Molecular Weight: 336.44

Elemental Analysis: C, 74.97; H, 7.19; N, 8.33; O, 9.51

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 450.00	Ready to ship
50mg	USD 750.00	Ready to ship
100mg	USD 1,250.00	Ready to ship
200mg	USD 2,250.00	Ready to ship

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Related CAS #

1197996-80-7 (free base) 1197397-89-9 (HCl)

Synonym

CBL0137; CBL-0137; CBL 0137; CBLC137; CBLC-137; CBLC 137; Curaxin 137.

IUPAC/Chemical Name

1,1'-(9-(2-(isopropylamino)ethyl)-9H-carbazole-3,6-diyl)bis(ethan-1-one)

InChi Key

JKCSODVERGVDLT-UHFFFAOYSA-N

InChi Code

InChI=1S/C21H24N2O2/c1-13(2)22-9-10-23-20-7-5-16(14(3)24)11-18(20)19-12-17(15(4)25)6-8-21(19)23/h5-8,11-13,22H,9-10H2,1-4H3

SMILES Code

CC(NCCN1C2=C(C3=C1C=CC(C(C)=O)=C3)C=C(C(C)=O)C=C2)C

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A23T01K12

QC Data

View QC data: current batch, Lot#A23T01K12

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

CBL0137 (Curaxin-137) is an inhibitor of the histone chaperone FACT (facilitates chromatin transcription) that simultaneously suppresses NF-κB and activates p53 with EC50 of 0.47 μM and 0.37 μM, respectively.

In vitro activity:

To test the effect of CBL0137 on gemcitabine-sensitive and -resistant PDA cells, MiaPaCa-2 and PANC-1 human PDA cell lines were used, which are gemcitabine-sensitive and resistant, respectively. Both cell lines were sensitive to CBL0137 in 72h viability assays (Fig.1A, B). Importantly, while treatment with CBL0137 led to complete absence of living cells at concentrations above 2.5 μM, gemcitabine treatment, which as reported was more effective against MiaPaCa-2 than PANC-1 cells, resulted in growth arrest rather than cell death since no reduction in the number of living cells was observed with dose escalation (Fig.1A, B). Consistent with this observation, there were no biochemical signs of cell death, such as caspase activation or PARP1 cleavage, when extracts of cells treated with gemcitabine using immunoblotting were analyzed, while the same signs were evident in extracts of cells treated with CBL0137 (Fig.1C, D). To test if CBL0137 could increase the toxicity of gemcitabine to sensitive and resistant cells, a colony forming assay was performed in which MiaPaCa-2 and PANC-1 cells which were treated for 4h with either drug alone or their combination. Surprisingly, CBL0137 caused a greater reduction in the number of colonies formed of not only MiaPaCa-2 cells when combined with gemcitabine, but also gemcitabine-resistant PANC-1 cells (Fig.1E, F). Thus, CBL0137 is toxic for pancreatic cancer cells independently of their sensitivity to gemcitabine and, moreover, is able to increase the sensitivity of both gemcitabine-sensitive and resistant PDA cells to gemcitabine. Reference: Oncotarget. 2014 Nov 30;5(22):11038-53. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25402820/

In vivo activity:

In order to determine whether the effect of CBL0137 monotherapy and combination with gemcitabine occurred in vivo, an orthotopic model of PANC-1, in which PANC-1 cells were inoculated directly into the tail of the pancreas of athymic nude mice, was utilized. Two weeks after inoculation, mice were treated for 4 weeks with 90 mg/kg CBL0137 intravenously (i.v.) once per week, 40 mg/kg gemcitabine intraperitoneally (i.p.) every 4th day (Q4d) or a combination of the two agents. A fourth treatment group received only the corresponding vehicles. One week following the end of treatment, mice were euthanized and tumors of the pancreas measured and then collected for histological analysis. While CBL0137 and gemcitabine monotherapy had only a modest effect on PANC-1 orthotopic tumor growth, which failed to reach statistical significance (39% and 20% growth inhibition, respectively), the combination of the two agents caused a substantial decrease in PANC-1 tumor growth (78% growth inhibition, P=0.0002; Fig. 2A). Histological examination of multiple sections of the pancreatic tissues from each mouse confirmed the anti-tumor effect of CBL0137 monotherapy and the combination and a more minor effect by gemcitabine (Fig. 2B). Based on the analysis, the vehicle control tumors were actively growing with numerous mitoses present. There were almost no apoptotic bodies and no evidence of necrosis or infiltration of lymphoid cells (Fig. 2B). There was also extensive tumor growth observed in the pancreases of the gemcitabine monotherapy mice with only single apoptotic tumor cells visible (Fig. 2B). In contrast, the CBL0137 monotherapy group and the CBL0137-gemcitabine combination group samples showed large necrotic fields, numerous apoptotic bodies and loss of tumor cells. In addition, there was infiltration of lymphoid cells into and adjacent to the remaining tumor (Fig. 2B). Thus CBL0137 demonstrated an anti-tumor effect in gemcitabine-resistant tumors and also potentiated the anti-tumor efficacy of gemcitabine when used in combination. Reference: Oncotarget. 2014 Nov 30;5(22):11038-53. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25402820/

	Solvent	mg/mL	mM
Solubility
	Ethanol	8.0	23.78

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 336.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Burkhart C, Fleyshman D, Kohrn R, Commane M, Garrigan J, Kurbatov V, Toshkov I, Ramachandran R, Martello L, Gurova KV. Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer. Oncotarget. 2014 Nov 30;5(22):11038-53. doi: 10.18632/oncotarget.2701. PMID: 25402820; PMCID: PMC4294371.

In vivo protocol:

1: Fleyshman D, Prendergast L, Safina A, Paszkiewicz G, Commane M, Morgan K, Attwood K, Gurova K. Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells. Oncotarget. 2017 Mar 28;8(13):20525-20542. doi: 10.18632/oncotarget.15656. PubMed PMID: 28423528; PubMed Central PMCID: PMC5400524. 2: Kim M, Neznanov N, Wilfong CD, Fleyshman DI, Purmal AA, Haderski G, Stanhope-Baker P, Burkhart CA, Gurova KV, Gudkov AV, Skitzki JJ. Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas. Cancer Res. 2016 Nov 15;76(22):6620-6630. doi: 10.1158/0008-5472.CAN-15-2764. Epub 2016 Sep 28. PubMed PMID: 27680682; PubMed Central PMCID: PMC5609527. 3: Maluchenko NV, Chang HW, Kozinova MT, Valieva ME, Gerasimova NS, Kitashov AV, Kirpichnikov MP, Georgiev PG, Studitsky VM. [Inhibiting the pro-tumor and transcription factor FACT: Mechanisms]. Mol Biol (Mosk). 2016 Jul-Aug;50(4):599-610. Russian. PubMed PMID: 27668600. 4: Lock R, Carol H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Wu J, Purmal A, Gudkov A, Kurmashev D, Kurmasheva RT, Houghton PJ, Smith MA. Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26263. Epub 2016 Sep 21. PubMed PMID: 27650817; PubMed Central PMCID: PMC5587189. 5: Barone TA, Burkhart CA, Safina A, Haderski G, Gurova KV, Purmal AA, Gudkov AV, Plunkett RJ. Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma. Neuro Oncol. 2017 Feb 1;19(2):186-196. doi: 10.1093/neuonc/now141. PubMed PMID: 27370399; PubMed Central PMCID: PMC5604960. 6: Dermawan JK, Hitomi M, Silver DJ, Wu Q, Sandlesh P, Sloan AE, Purmal AA, Gurova KV, Rich JN, Lathia JD, Stark GR, Venere M. Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models. Cancer Res. 2016 Apr 15;76(8):2432-42. doi: 10.1158/0008-5472.CAN-15-2162. Epub 2016 Feb 26. PubMed PMID: 26921329; PubMed Central PMCID: PMC4873320. 7: Carter DR, Murray J, Cheung BB, Gamble L, Koach J, Tsang J, Sutton S, Kalla H, Syed S, Gifford AJ, Issaeva N, Biktasova A, Atmadibrata B, Sun Y, Sokolowski N, Ling D, Kim PY, Webber H, Clark A, Ruhle M, Liu B, Oberthuer A, Fischer M, Byrne J, Saletta F, Thwe le M, Purmal A, Haderski G, Burkhart C, Speleman F, De Preter K, Beckers A, Ziegler DS, Liu T, Gurova KV, Gudkov AV, Norris MD, Haber M, Marshall GM. Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Sci Transl Med. 2015 Nov 4;7(312):312ra176. doi: 10.1126/scitranslmed.aab1803. PubMed PMID: 26537256. 8: Burkhart C, Fleyshman D, Kohrn R, Commane M, Garrigan J, Kurbatov V, Toshkov I, Ramachandran R, Martello L, Gurova KV. Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer. Oncotarget. 2014 Nov 30;5(22):11038-53. PubMed PMID: 25402820; PubMed Central PMCID: PMC4294371. 9: Gasparian AV, Burkhart CA, Purmal AA, Brodsky L, Pal M, Saranadasa M, Bosykh DA, Commane M, Guryanova OA, Pal S, Safina A, Sviridov S, Koman IE, Veith J, Komar AA, Gudkov AV, Gurova KV. Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT. Sci Transl Med. 2011 Aug 10;3(95):95ra74. doi: 10.1126/scitranslmed.3002530. PubMed PMID: 21832239.