TBB

Names

[ Name ]:
TBB

[Synonym ]:
4,5,6,7-Tetrabromo-1H-benzotriazole
4,5,6,7-Tetrabromobenzotriazole
4,5,6,7-tetrabromo-2H-benzotriazole
4,5,6,7-Tetrabromo-2-azabenzimidazole 4,5,6,7-Tetrabromobenzotriazole
1H-1,2,3-Benzotriazole, 4,5,6,7-tetrabromo-
4,5,6,7-tetrabromo-2-azabenzimidazole
4,5,6,7-Tetrabromo-2-azabenzimidazole,4,5,6,7-Tetrabromobenzotriazole
TBB
NSC 231634
1H-Benzotriazole,4,5,6,7-tetrabromo-

Biological Activity

[Description]:

TBB is a cell-permeable and ATP-competitive CK2 inhibitor with an IC50 of 0.15 μM for rat liver CK2.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Casein Kinase

Signaling Pathways >> Stem Cell/Wnt >> Casein Kinase

Research Areas >> Cancer

[Target]

CK2:0.15 μM (IC50, Human CK2)

PIM1:1.04 μM (IC50)

PIM2:4.3 μM (IC50)

PIM3:0.86 μM (IC50)

HIPK2:5.3 μM (IC50)

HIPK3:4.9 μM (IC50)

DYRK1a:4.36 μM (IC50)

DYRK2:0.99 μM (IC50)

DYRK3:5.3 μM (IC50)

PKD1:5.9 μM (IC50)

CDK2:14 μM (IC50)

[In Vitro]

Investigation of the inhibitory power of TBB with a panel of 33 protein kinases shows highest potency for CK2 (casein kinase 2) (human CK2: IC50=1.6 μM at 100 μM ATP). TBB also inhibits three other kinases with less potency: CDK2 (IC50=15.6 μM), phosphorylase kinase (IC50=8.7 μM) and glycogen synthase kinase 3β (GSK3β) (IC50=11.2 μM). All other kinases tested have IC50 values 50-fold greater than that for CK2[1]. The viability of the androgen insensitive PC-3 cells may be diminished by TBB (60 μM TBB) acting either alone or combined with anticancer agents CPT or TRAIL when a proper time schedule of the administration is applied. The time schedule-dependent activity of TBB does not come from its effect on apoptosis in PC-3 cells[2]. TBB is an ATP/GTP competitive inhibitor of protein kinase casein kinase-2 (CK2), has been examined against a panel of 33 protein kinases, either Ser/Thr- or Tyr-specific. In the presence of 10 μM TBB (and 100 μM ATP) only CK2 is drastically inhibited (>85%) whereas three kinases (phosphorylase kinase, glycogen synthase kinase 3L and cyclin-dependent kinase 2/cyclin A) underwent moderate inhibition, with IC50 values one-two orders of magnitude higher than CK2 (IC50=0.9 μM). TBB also inhibits endogenous CK2 in cultured Jurkat cells[3].

[In Vivo]

The extent of retinal neovascularization in a mouse OIR model is reduced by approximately 60% after treatment with TBB (6 days at 60 mg/kg per day)[4].

[Cell Assay]

PC-3 or HeLa cells are cultured routinely in RPMI-1640 and DMEM media, respectively, which are supplemented with 10% FBS, Penicillin (100 U/mL) and Streptomycin (100 μg/mL) at 37°C in a humidified atmosphere of 5% CO2. Cells are seeded at 5×104 cells/well (PC-3) or 2×104 (HeLa) in 24-wells plates and cultured for 72 h. TBB (final concentration 60 μM), CPT (final concentration 5.8 nM), 2-deoxyglucose (2-DG; final concentration 0.5 mM) or TRAIL (final concentration 13.3 ng/mL) are added to the medium individually or in a combination and the cells are cultured for additional time, indicated on each figure. After treatment, the medium with the agent is removed and 500 μL of MTT mixture (0.5 mg/mL for PC-3 and 5.0 mg/mL for HeLa cells in medium without phenol red) is added to each well and incubated for an additional 1 h at 37°C. The formazan crystals are diluted in 250 μL of DMSO. The absorbance is measured at 570 nm[2].

[Animal admin]

Mice[4] The heterozygous C57BL/6J mice are used. Emodin and TBB are injected intraperitoneally in volumes of 50 μL or less per mouse at doses of 15 to 30 mg/kg body weight, twice daily, starting from day 11. Control mice are injected with PEG-Tween vehicle alone.

[References]

[1]. De Moliner E, et al. Alternative binding modes of an inhibitor to two different kinases. Eur J Biochem. 2003 Aug;270(15):3174-81.

[2]. Orzechowska E, et al. Time schedule-dependent effect of the CK2 inhibitor TBB on PC-3 human prostate cancer cell viability. Oncol Rep. 2012 Jan;27(1):281-5.

[3]. Sarno S, et al. Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ('casein kinase-2'). FEBS Lett. 2001 May 4;496(1):44-8.

[4]. Ljubimov AV, et al. Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4583-91.

[5]. Pagano MA, et al. The selectivity of inhibitors of protein kinase CK2: an update. Biochem J. 2008 Nov 1;415(3):353-65.

[6]. Chen Z, et al. CK2α promotes advanced glycation end products-induced expressions of fibronectin and intercellular adhesion molecule-1 via activating MRTF-A in glomerular mesangial cells. Biochem Pharmacol. 2017 Dec 6;148:41-51.

[Related Small Molecules]

Silmitasertib (CX-4945) | D4476 | DMAT | Emodin | PF-670462 | SR 3029 | IC 261 | TA-01 | Ellagic acid | TTP 22 | LH846 | Casein Kinase II Inhibitor IV | PF 4800567

Chemical & Physical Properties

[ Density]:
2.8±0.1 g/cm3

[ Boiling Point ]:
552.5±45.0 °C at 760 mmHg

[ Melting Point ]:
262-266ºC

[ Molecular Formula ]:
C₆HBr₄N₃

[ Molecular Weight ]:
434.708

[ Flash Point ]:
288.0±28.7 °C

[ Exact Mass ]:
430.690369

[ PSA ]:
41.57000

[ LogP ]:
3.96

[ Vapour Pressure ]:
0.0±1.5 mmHg at 25°C

[ Index of Refraction ]:
1.801

MSDS

Click to get detail MSDS

Safety Information

[ Personal Protective Equipment ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ Hazard Codes ]:
Xi

[ RIDADR ]:
NONH for all modes of transport

[ HS Code ]:
2933990090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Articles

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation.

Autophagy 11 , 1308-25, (2015)

Recent studies have shown that the phosphorylation and dephosphorylation of ULK1 and ATG13 are related to autophagy activity. Although ATG16L1 is absolutely required for autophagy induction by affecti...

Casein Kinase 2 Negatively Regulates Abscisic Acid-Activated SnRK2s in the Core Abscisic Acid-Signaling Module.

Mol. Plant 8 , 709-21, (2015)

SnRK2 kinases, PP2C phosphatases and the PYR/PYL/RCAR receptors constitute the core abscisic acid (ABA) signaling module that is thought to contain all of the intrinsic properties to self-regulate the...

Identification of malaria parasite-infected red blood cell surface aptamers by inertial microfluidic SELEX (I-SELEX).

Sci. Rep. 5 , 11347, (2015)

Plasmodium falciparum malaria parasites invade and remodel human red blood cells (RBCs) by trafficking parasite-synthesized proteins to the RBC surface. While these proteins mediate interactions with ...

TBB