UK-5099

Names

[ Name ]:
UK-5099

[Synonym ]:
CS-1048
(2E)-2-Cyano-3-(1-phenyl-1H-indol-3-yl)acrylic acid
2-Propenoic acid, 2-cyano-3-(1-phenyl-1H-indol-3-yl)-, (2E)-
UK-5099
2-Cpiya

Biological Activity

[Description]:

UK-5099 is a potent inhibitor of the mitochondrial pyruvate carrier (MPC). UK-5099 ihibits pyruvate-dependent O2 consumption with an IC50 of 50 nM.

[Related Catalog]:

Signaling Pathways >> Membrane Transporter/Ion Channel >> Monocarboxylate Transporter

Research Areas >> Cancer

[Target]

IC50: 50 nM (MPC)[1]

[In Vitro]

The trypanosomal pyruvate carrier is found to be rather insensitive to inhibition by alpha-cyano-4-hydroxycinnamate (Ki=17 mM) but can be completely blocked by UK-5099 (Ki=49 microM)[2]. UK-5099 also inhibits the monocarboxylate transporter (MCT) [3]. UK5099 significantly inhibits the glucose-stimulated rise in oxygen consumption in a dose-dependent manner and at 150 μM reduced oxygen consumption below basal levels. UK5099 reduces ATP levels and increases ADP and AMP levels in 832/13 cells[4]. The UK5099 treated cells show significantly higher proportion of side population fraction and express higher levels of stemness markers Oct3/4 and Nanog. UK5099 application may be an ideal model for Warburg effect studies[5].

[In Vivo]

The MPC inhibitor UK5099 increases the glucose excursion seen during an intraperitoneal glucose tolerance test in C57BLK mice[4].

[Cell Assay]

The 832/13 cell line derived from INS-1 rat insulinoma cells is used for experiments. Cell viability is measured using CellTiter Blue. The assay is based on cellular reduction of resazurin to resorufin. Appearance of resorufin is monitored by fluorescence emission at 585 nm using a Spectramax M5 microplate reader with excitation at 555 nm. For UK5099-treated cells, cells are allowed to recover for 1 h before measuring cell viability. Data are expressed as -fold relative to no treatment or siCtrl[4].

[Animal admin]

C57BLK mice are fasted for 16 h prior to glucose challenge. UK5099 (32 μmol/kg of body weight) or DMSO in PBS is injected into the intraperitoneal cavity 30 min before injecting glucose (1.5 mg of glucose/g of body weight). Blood glucose levels are measured at 0, 10, 20, 30, 60, and 120 min after glucose injection[4].

[References]

[1]. Halestrap AP. The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J. 1975 April; 148(1): 85-96.

[2]. Wiemer EA, et al. The inhibition of pyruvate transport across the plasma membrane of the bloodstream form of Trypanosoma brucei and its metabolic implications. Biochem J. 1995 Dec 1;312 ( Pt 2):479-84.

[3]. Hinoi E, et al. A molecular mechanism of pyruvate protection against cytotoxicity of reactive oxygen species in osteoblasts. Mol Pharmacol. 2006 Sep;70(3):925-35. Epub 2006 Jun 9.

[4]. Patterson JN, et al. Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion. J Biol Chem. 2014 May 9;289(19):13335-46.

[5]. Zhong Y, et al. Application of mitochondrial pyruvate carrier blocker UK5099 creates metabolic reprogram and greater stem-like properties in LnCap prostate cancer cells in vitro. Oncotarget. 2015 Nov 10;6(35):37758-69.

[Related Small Molecules]

AZD3965 | AR-C155858 | 7-Diethylaminocoumarin-3-carboxylic acid | 7ACC2

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
448.6±45.0 °C at 760 mmHg

[ Molecular Formula ]:
C₁₈H₁₂N₂O₂

[ Molecular Weight ]:
288.300

[ Flash Point ]:
225.1±28.7 °C

[ Exact Mass ]:
288.089874

[ PSA ]:
68.85000

[ LogP ]:
4.60

[ Vapour Pressure ]:
0.0±1.1 mmHg at 25°C

[ Index of Refraction ]:
1.634

[ Storage condition ]:
-20℃

MSDS

Click to get detail MSDS

Safety Information

[ Hazard Statements ]:
H413

[ RIDADR ]:
NONH for all modes of transport

Articles

Whole cell Cl- currents in human neutrophils induced by cell swelling.

Am. J. Physiol. 265(1 Pt 1) , C156-65, (1993)

The properties of the conductive Cl- transport pathway underlying regulatory volume decrease (RVD) in human neutrophils were investigated using the whole cell patch-clamp technique. Cell swelling was ...

Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

J. Biol. Chem. 289(19) , 13335-46, (2014)

It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason...

Interleukin-1beta secretion is impaired by inhibitors of the Atp binding cassette transporter, ABC1.

Blood 90(8) , 2911-5, (1997)

The production of interleukin-1beta (IL-1beta), a powerful mediator of inflammation, is tightly regulated at several levels. However, in some pathologic conditions, a pharmacologic treatment is requir...