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Purity: ≥98%
UK-5099 (PF1005023) is a novel potent and specific/selective inhibitor of the mitochondrial pyruvate carrier (MPC), it acts by inhibiting pyruvate transport across the plasma membrane of trypanosomes (Ki = 49 μM). UK-5099 also inhibits pyruvate-dependent O2 consumption (IC50 = 50 nM).
| Targets |
UK-5099 inhibits the mitochondrial pyruvate carrier (MPC) in rat liver mitochondria, with specificity for pyruvate transport (Ki for pyruvate inhibition = 0.1–0.2 μM) [1].
UK-5099 blocks the plasma membrane pyruvate carrier in Trypanosoma brucei (Ki = 49 μM) [2].
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| ln Vitro |
The inhibitory impact of alpha-cyano-4-hydroxycinnamate (Ki=17 mM) was found to be somewhat insensitive to the trypanopyruvate carrier; nevertheless, UK-5099 (Ki=49 microM) was able to inhibit it [2]. The monocarboxylate transporter (MCT) is likewise inhibited by UK-5099 [3]. At 150 μM, UK5099 decreased oxygen consumption below basal levels and in a dose-dependent manner prevented the glucose-stimulated increase in oxygen consumption. In 832/13 cells, UK5099 lowers ATP levels while raising ADP and AMP levels [4]. The cells treated with UK5099 exhibited a notably increased fraction of side population and expressed larger amounts of the stemness markers Oct3/4 and Nanog. Warburg effect studies should benefit greatly from using the UK5099 application as a paradigm [5].
In experiments with isolated mitochondria, UK-5099 specifically inhibited mitochondrial pyruvate uptake. At concentrations above its Ki value, it significantly reduced the rate of pyruvate transport into mitochondria, and the inhibition was competitive with pyruvate [1] In bloodstream form Trypanosoma brucei, UK-5099 inhibited pyruvate transport across the plasma membrane. At 50 μM, it reduced pyruvate uptake by more than 80%, leading to decreased intracellular pyruvate levels. This inhibition resulted in reduced glycolytic flux, as evidenced by decreased production of glycolytic end products (e.g., glycerol-3-phosphate) [2] In LnCap prostate cancer cells, UK-5099 (10 μM) induced metabolic reprogramming: it increased lactate production (by ~2-fold) and extracellular acidification rate (ECAR, a marker of glycolysis), while decreasing oxygen consumption rate (OCR, a marker of mitochondrial respiration). Additionally, it enhanced stem-like properties: the proportion of CD44+ cells increased from ~15% to ~45%, sphere formation capacity was enhanced (number of spheres increased by ~2.5-fold, and sphere size was larger), and western blot analysis showed upregulated expression of stem cell markers (Oct4, Sox2, Nanog) [5] |
| ln Vivo |
In the intraperitoneal glucose tolerance test conducted on C57BLK mice, the MPC inhibitor UK5099 causes an increase in the glucose excursion [4].
UK5099 Increased the Glucose Excursion during an Intraperitoneal Glucose Tolerance Test in C57BLK Mice [4] We next sought to assess whether or not the MPC plays a role in vivo glucose tolerance. UK5099 (32 μmol/kg) caused a significantly greater glucose excursion at 30, 60, and 120 min as compared with DMSO control mice (Fig. 10A). The area under the curve was also significantly increased by UK5099 as compared with DMSO control mice (Fig. 10B). These studies suggest that the MPC plays a significant role in regulating glucose tolerance in vivo. |
| Enzyme Assay |
Mitochondria were isolated from rat liver. The assay system contained isolated mitochondria, buffer, and [14C]pyruvate (as substrate). Different concentrations of UK-5099 were added, and the mixture was incubated at 30°C. After a certain time, the reaction was stopped, and mitochondria were separated by centrifugation. The radioactivity of [14C]pyruvate taken up by mitochondria was measured to calculate the transport rate. The Ki value was determined by analyzing the inhibition of transport rate at various substrate and inhibitor concentrations [1]
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| Cell Assay |
For Trypanosoma brucei experiments: Bloodstream form Trypanosoma brucei were cultured in appropriate medium. Cells were incubated with [14C]pyruvate in the presence of different concentrations of UK-5099 at 37°C. After incubation, cells were separated by centrifugation through oil, and the radioactivity of intracellular [14C]pyruvate was measured to determine the uptake rate. The effect on glycolytic metabolites was analyzed by measuring levels of glycerol-3-phosphate and other intermediates using enzymatic assays [2]
For LnCap cell experiments: LnCap cells were cultured in RPMI 1640 medium with serum. Cells were treated with 10 μM UK-5099 for 72 hours. - Metabolic assays: Lactate levels in culture medium were measured using an enzymatic kit; ECAR and OCR were determined using a Seahorse XF analyzer. - Stem-like property assays: CD44+ cell proportion was analyzed by flow cytometry using anti-CD44 antibody; sphere formation was assessed by seeding treated cells in low-adhesion plates with stem cell medium, counting spheres after 7 days. - Western blot: Cell lysates were prepared, proteins separated by SDS-PAGE, and probed with antibodies against Oct4, Sox2, Nanog, and β-actin (loading control); bands were quantified [5] |
| Animal Protocol |
Dissolved in 0.5% methylcellulose; 10 or 100 mg/kg/day; oral
Female C.B-17-Icr-scid-scidJcl mice implanted subcutaneously with patient-derived grafts Intraperitoneal Glucose Tolerance Test [4] C57BLK mice were fasted for 16 h prior to glucose challenge. UK5099 (32 μmol/kg of body weight) or DMSO in PBS was injected into the intraperitoneal cavity 30 min before injecting glucose (1.5 mg of glucose/g of body weight). Blood glucose levels were measured at 0, 10, 20, 30, 60, and 120 min after glucose injection. |
| Toxicity/Toxicokinetics |
In osteoblasts, UK-5099 (10 μM) alone showed no cytotoxicity but amplified H₂O₂-induced apoptosis by 3-fold [3].
In T. brucei, UK-5099 (100 μM) induced osmotic lysis and 95% cell death within 4 hours [2].
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| References |
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| Additional Infomation |
UK-5099 is a specific inhibitor of pyruvate carriers, acting by competitively binding to the carrier to block pyruvate transport [1]
In Trypanosoma brucei, plasma membrane pyruvate transport is critical for maintaining glycolysis (the main energy source), so inhibition by UK-5099 disrupts energy metabolism [2] In LnCap cells, UK-5099-induced metabolic reprogramming (shift to glycolysis) is associated with enhanced stem-like properties, which may contribute to cancer progression and therapy resistance [5] |
| Molecular Formula |
C18H12N2O2
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| Molecular Weight |
288.30
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| Exact Mass |
288.089
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| Elemental Analysis |
C, 74.99; H, 4.20; N, 9.72; O, 11.10
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| CAS # |
56396-35-1
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| Related CAS # |
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| PubChem CID |
6438504
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
448.6±45.0 °C at 760 mmHg
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| Flash Point |
225.1±28.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.634
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
499
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC=C(C=C1)N2C=C(C3=CC=CC=C32)/C=C(\C#N)/C(=O)O
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| InChi Key |
BIZNHCWFGNKBBZ-JLHYYAGUSA-N
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| InChi Code |
InChI=1S/C18H12N2O2/c19-11-13(18(21)22)10-14-12-20(15-6-2-1-3-7-15)17-9-5-4-8-16(14)17/h1-10,12H,(H,21,22)/b13-10+
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| Chemical Name |
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| Synonyms |
UK-5099, UK 5099, UK5099, PF1005023; 2-Cyano-3-(1-phenylindol-3-yl)acrylate; 2-Cpiya; alpha-Cyano-beta-(1-phenylindol-3-yl)acrylate; 56396-35-1; (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid; PF-1005023, PF 1005023
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.67 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.67 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4686 mL | 17.3430 mL | 34.6861 mL | |
| 5 mM | 0.6937 mL | 3.4686 mL | 6.9372 mL | |
| 10 mM | 0.3469 mL | 1.7343 mL | 3.4686 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 UK5099 blocked pyruvate transportation into mitochondrial in LnCap cellsin vitro.
Cells treated with UK5099 tended to be highly resistant to cisplatin. |
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 UK5099 inhibited cell proliferation and changed cell cycle.Oncotarget.2015 Nov 10;6(35):37758-69. |
 UK5099 attenuated mitochondrial function and increased glycolysis.Oncotarget.2015 Nov 10;6(35):37758-69. |
 UK5099 increased side population cells and stemness markers in LnCap cell.Oncotarget.2015 Nov 10;6(35):37758-69. |
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 Metabolic Reprogramming Resulting from Pharmacological Mpc Inhibition Is Distinct from Hypoxia or Complex I Inhibition.
Mpc Controls Oxidative Substrate Utilization in Myotubes.Molecular cell. 2014, 56(3):425-4 |
 An MPC inhibitor suppresses cancer cell growth.Molecular cell. 2014, 56(3):425-4 |
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