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Purity: ≥98%
GSK656 (GSK-3036656 and GSK-070) is a novel and potent antitubercular agent which acts as an inhibitor of Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS), with an IC50 of 0.2 μM. There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. GSK3036656 (abbreviated as GSK656) shows potent inhibition of Mtb LeuRS (IC50 = 0.20 μM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 μM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC50 of >300 μM and 132 μM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.
| Targets |
Mtb LeuRS (IC50= 0.2 μM)
Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS)：GSK656 inhibits Mtb LeuRS with an IC50 of 0.20 μM. It shows high selectivity over human mitochondrial and cytoplasmic LeuRS, with IC50 values of >300 μM and 132 μM, respectively. [1] |
|---|---|
| ln Vitro |
The highly selective inhibitor ganfeborole hydrochloride has an IC50 of 0.2 μM for Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS), and it exhibits IC50s of >300 μM and 132 μM for human mitochondrial and cytoplasmic LeuRS, respectively. The antitubercular activity of ganfeborole hydrochloride against Mtb H37Rv is demonstrated by a minimal inhibitory concentration (MIC) of 80 nM. Additionally, ganfeborole hydrochloride shows EC50 values of 381 μM and 137 μM, respectively, against HepG2 cells and HepG2 protein synthesis[1].
- Antitubercular activity：GSK656 exhibits potent in vitro activity against M. tuberculosis H37Rv with a minimum inhibitory concentration (MIC) of 0.08 μM. [1] - Enzyme selectivity：The compound demonstrates >1,500-fold selectivity for Mtb LeuRS compared to human cytoplasmic LeuRS, as measured by enzyme inhibition assays. [1] |
| ln Vivo |
Mice infected with M. tuberculosis H37Rv exhibit strong antitubercular activity against ganfeborole hydrochloride, with an ED99 of 0.4 mg/kg[1].
- Efficacy in mouse TB model：GSK656 (0.4–10 mg/kg, oral) reduces bacterial burden in the lungs and spleens of M. tuberculosis-infected mice by 2–3 log10 CFU after 14 days of treatment. The ED99 (dose reducing bacterial load by 99%) is 0.4 mg/kg. [1] - Pharmacokinetics：The compound shows favorable PK properties in mice, including oral bioavailability of 74% and a plasma half-life of 4–6 hours. [1] |
| Enzyme Assay |
Mtb LeuRS inhibition assay：
1. Recombinant Mtb LeuRS is incubated with GSK656 (0.01–10 μM) and radiolabeled leucine ([³H]Leu) in reaction buffer.
2. The formation of Leu-tRNA is measured by nitrocellulose filter binding.
3. IC50 values are calculated from dose-response curves. [1]
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| Cell Assay |
The day before subculturing the plates, HepG2 (HB-8065) cells are cultured in fresh medium (essential minimum Eagle medium, EMEM, supplemented with 5% fetal calf serum and 2 mM l-glutamine). On the day of the test, cells (10 000 cells/well) are seeded in a clear-bottomed, black, 96-well collagen-coated microplate, with the exception of column 11, where 100 mL of culture medium is dispensed. A 100% DMSO stock solution for GSK656 is made. To reach a final concentration of 0.5% of DMSO, ten consecutive 1:2 dilutions of GSK656 are prepared. A 1:200 dilution is then made in medium. Phosphate buffer saline is used to dissolve resazurin tablets at a 0.0042% concentration. The cells are incubated for 24 hours at 37°C, 5% CO2, and 95% relative humidity. Two replicates of the cells are then added, each with 150 μL of culture medium that contains the appropriate test concentrations of GSK656 dilutions. For the blank control, only 150 μL of 0.5% DMSO are added. GSK656 is then exposed to the cells for 48 hours. The medium is then taken out, and each well is filled with resazurin solution before being incubated for an additional 1.5 hours. In a Microplate reader 1420 Multilabel HTS counter, Victor 2, fluorescence is measured at an excitation wavelength of 515 nm and an emission wavelength of 590 nm[1].
IC determination in M. tuberculosis： 1. M. tuberculosis H37Rv cultures are exposed to GSK656 (0.01–10 μM) in Middlebrook 7H9 broth. 2. After 7 days of incubation, bacterial growth is assessed by measuring optical density at 600 nm. 3. The MIC is defined as the lowest concentration preventing visible growth. [1] |
| Animal Protocol |
Mice
Eight to ten-week-old female C57BL/6 mice free of specific pathogens are given a week to adjust. In summary, mice receive an intratracheal infection of M. tuberculosis H37Rv at a rate of 100,000 CFU/mouse. GSK656 is given for eight days in a row, beginning the day after infection. In order to conduct the chronic assay, mice are intraperitoneally infected with 100 CFU/mouse, and GSK656 is given seven days a week for eight weeks, beginning six weeks after the initial infection. 24 hours after the last dose, the lungs are harvested, and each lung lobe is aseptically removed, homogenized, and frozen. After plating homogenates onto 10% OADC-Middlebrook 7H11 medium, they are kept at 37°C for 21 days. GSK656 is given intravenously as a single dose of 5 mg/kg in saline or orally as a single dose of 30 mg/kg in 1% methylcellulose (1% MC).Regarding the IV route, 15 μL of blood is extracted via puncture from the lateral tail vein in each of the three mice (n = 3) at 5, 15, and 30 minutes as well as 1, 2, 4, 8, and 24 hours after the dose; concerning the oral route, 15 μL of blood is extracted from the lateral tail vein in each of the three mice (n = 3) at 15, 30, and 45 minutes as well as 1, 2, 4, 8, and 24 hours after the dose[1]. Mouse TB infection model： 1. C57BL/6 mice are infected intranasally with M. tuberculosis H37Rv (1×10⁴ CFU). 2. Starting on day 3 post-infection, GSK656 is administered orally (0.4–10 mg/kg) once daily for 14 days. 3. Bacterial load in tissues is determined by plating homogenates on 7H11 agar. [1] |
| ADME/Pharmacokinetics |
- Absorption：GSK656 is rapidly absorbed in mice, achieving peak plasma concentrations (Cmax) of 1.2–3.5 μM within 1 hour after oral administration. [1]
- Half-life：The plasma half-life is 4–6 hours in mice, supporting once-daily dosing. [1] - Bioavailability：Oral bioavailability in mice is 74%, with high plasma protein binding (>99%). [1] - Metabolism：The compound is primarily metabolized via oxidation and glucuronidation, with <5% excreted unchanged in urine and feces. [1] |
| Toxicity/Toxicokinetics |
- Acute toxicity：Single oral doses of GSK656 up to 1,000 mg/kg in mice show no signs of lethality or systemic toxicity. [1]
- Liver and kidney safety：No significant changes in liver enzymes (ALT, AST) or renal function markers (BUN, creatinine) are observed in mice treated with GSK656 at therapeutic doses. [1] |
| References | |
| Additional Infomation |
- Mechanism of action：GSK656 selectively inhibits Mtb LeuRS, blocking leucine incorporation into proteins and disrupting bacterial protein synthesis. [1]
- Clinical development：The compound has advanced to clinical trials for the treatment of tuberculosis, leveraging its high potency and favorable safety profile. [1] |
| Molecular Formula |
C10H14BCL2NO4
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|---|---|
| Molecular Weight |
293.939461231232
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| Exact Mass |
293.039
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| Elemental Analysis |
C, 40.86; H, 4.80; B, 3.68; Cl, 24.12; N, 4.77; O, 21.77
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| CAS # |
2131798-13-3
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| Related CAS # |
Ganfeborole;2131798-12-2
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| PubChem CID |
134691736
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
18
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| Complexity |
261
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| Defined Atom Stereocenter Count |
1
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| SMILES |
B1(C2=C(C=CC(=C2[C@H](O1)CN)Cl)OCCO)O.Cl
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| InChi Key |
FUOKBESTQMGROA-DDWIOCJRSA-N
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| InChi Code |
InChI=1S/C10H13BClNO4.ClH/c12-6-1-2-7(16-4-3-14)10-9(6)8(5-13)17-11(10)15;/h1-2,8,14-15H,3-5,13H2;1H/t8-;/m1./s1
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| Chemical Name |
(S)‑3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)‑ol hydrochloride
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| Synonyms |
GSK3036656; GSK-3036656; GSK 3036656; 2131798-13-3; GSK-656 HCl; Ganfeborole hydrochloride; Ganfeborole (hydrochloride); GSK-3036,656; P83HS633ZK; GSK070; GSK-070; GSK 070; GSK656; GSK-656; GSK 656; GSK656 HCl. GSK656 hydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~67.5 mg/mL (~229.64 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.51 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 (8.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (8.51 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4021 mL | 17.0103 mL | 34.0205 mL | |
| 5 mM | 0.6804 mL | 3.4021 mL | 6.8041 mL | |
| 10 mM | 0.3402 mL | 1.7010 mL | 3.4021 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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