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| Other Sizes |
| Targets |
IC50s: 35 nM (PDK-1), 40 nM (PDK-3), 84 nM (PDK-2), 91 nM (PDK-4)[1]
VER-246608 targets all four pyruvate dehydrogenase kinase (PDK) isoforms: PDK1, PDK2, PDK3, and PDK4. It is an ATP-competitive inhibitor, meaning it competes with ATP for binding to the kinase's active site. By inhibiting PDK, it prevents the phosphorylation and inactivation of pyruvate dehydrogenase (PDH), keeping it in its active, dephosphorylated form. |
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| ln Vitro |
VER-246608 is a brand-new ATP competitive pan-subtype PDK inhibitor. In a DELFIA-based enzyme functional assay, VER-246608 showed comparable potency against all four PDK isoforms in the sub-100 nM range. With an IC50 value of 266 nM, VER-246608 suppresses the phosphorylation of E1α at the Ser293 position, which is phosphorylated by all four PDK isoenzymes, in terms of cellular biomarker regulation. After an hour of incubation, PC-3 cells treated with 9 μM and 27 μM VER-246608 showed a 21% and 42% drop in the medium L-lactate content. At the same concentration where VER-246608 inhibits L-lactate synthesis, it also reduces D-glucose consumption. The sphere volume decreased by almost 50% at concentrations of 10 μM and beyond, suggesting that VER-246608 is more potent than monolayer growth [1].
In vitro, VER-246608 inhibits PDK1, PDK2, PDK3, and PDK4 with IC50 values of 35, 84, 40, and 91 nM, respectively. It is selective for PDKs over Hsp90 (IC50 > 10 µM) and a panel of 97 kinases at 10 µM. At concentrations of 10 and 20 µM, it decreases L-lactate production in PC3 cells. |
| ln Vivo |
In vivo, VER-246608 has anticancer activity in preclinical models. It disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells. Treatment of four cancer cell lines (PC-3, SW-1088, UM-22B, and MEF) under depleted glucose/glutamine conditions resulted in almost complete inhibition of cell growth.
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| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for VER-246608 involve measuring PDK enzymatic activity using purified recombinant PDK isoforms. The enzyme is incubated with a substrate (e.g., pyruvate dehydrogenase) and ATP in the presence of varying concentrations of VER-246608. Kinase activity is measured by ADP production or phosphorylation of the substrate, and IC50 values are calculated.
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| Cell Assay |
Compound cytotoxicity is determined using the Sulforhodamine B assay for cells cultured as a monolayer. For spheroid growth experiments, PC-3 cells are seeded (500 cells/well) into 96 well round bottom plates in RPMI-1640 media containing 2.5% (w/v) Matrigel. The resultant spheroids are treated with VER-246608 (2.5, 5, 10, 20, and 40 μM) 48 h post-seeding. Spheroid volumes are determined by obtaining diameter measurements from images taken on a Zeiss Axiovert 200 M inverted microscope using the axiovision software[1]. |
| Animal Protocol |
In vivo animal experiments for VER-246608 are performed in xenograft mouse models of cancer. VER-246608 is administered, and tumor growth, PDK inhibition, metabolic markers, and survival are assessed. Efficacy is compared to vehicle control.
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| ADME/Pharmacokinetics |
VER-246608 has good bioavailability and systemic exposure. Detailed pharmacokinetic parameters are available from preclinical studies. It is suitable for in vivo efficacy studies.
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| Toxicity/Toxicokinetics |
VER-246608 is well-tolerated at efficacious doses in preclinical studies. No significant off-target toxicity has been reported. It is selective for PDKs over other kinases.
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| References | |
| Additional Infomation |
Inhibits pyruvate dehydrogenase kinase; structure can be found in the first article.
VER-246608 is a research compound for cancer metabolism. It is a valuable tool for studying the role of PDK in metabolic reprogramming and tumor growth. It is not approved for clinical use. |
| Molecular Formula |
C28H23CLF2N4O4
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|---|---|
| Molecular Weight |
552.956432580948
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| Exact Mass |
552.137
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| CAS # |
1684386-71-7
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| PubChem CID |
86280454
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| Appearance |
White to off-white solid powder
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| LogP |
5.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
810
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=NC=C(C)C(C2C=CC(=CC=2)N(C(C2C=CC(=CC=2O)O)=O)CC2C=CC(CNC(C(F)F)=O)=CC=2)=N1
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| InChi Key |
LCGNLQSOSJFLKR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H23ClF2N4O4/c1-16-13-33-28(29)34-24(16)19-6-8-20(9-7-19)35(27(39)22-11-10-21(36)12-23(22)37)15-18-4-2-17(3-5-18)14-32-26(38)25(30)31/h2-13,25,36-37H,14-15H2,1H3,(H,32,38)
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| Chemical Name |
N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-[[4-[[(2,2-difluoroacetyl)amino]methyl]phenyl]methyl]-2,4-dihydroxybenzamide
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| Synonyms |
VER246608 VER 246608 VER-246608
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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 |
| 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) |
DMSO : ~100 mg/mL (~180.84 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.52 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 (4.52 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 | 1.8084 mL | 9.0422 mL | 18.0845 mL | |
| 5 mM | 0.3617 mL | 1.8084 mL | 3.6169 mL | |
| 10 mM | 0.1808 mL | 0.9042 mL | 1.8084 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.
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