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Purity: ≥98%
KM11060 is a novel mutated corrector of the F508del-CFTR (cystic fibrosis transmembrane conductance regulator) trafficking defect. It corrects F508del-CFTR trafficking, and increases the amount of functional CFTR at the plasma membrane (~75%) and inhibits PDE5 activity. Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics. KM11060 partially corrects F508del-CFTR processing and increases surface expression to 75% of that observed in cells incubated at low temperature. Up to 50% of the F508del-CFTR in cells treated with KM11060 was complex-glycosylated, indicating passage through the Golgi. KM11060 as a promising compound for further development of CF therapeutics.
| Targets |
CFTR/cystic fibrosis transmembrane conductance regulator
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| ln Vitro |
Pharmacological tools like KM11060, which are small-molecule correctors, could be beneficial in researching the F508del-CFTR processing problem and developing treatments for cystic fibrosis. In both native epithelial tissues and cultured cells, KM11060 restores F508del-CFTR trafficking. F508del-CFTR processing is largely corrected by KM11060, which also raises surface expression to 75% of what is seen in cells cultured at low temperature. In cells treated with KM11060, up to 50% of the F508del-CFTR was complex-glycosylated, indicating Golgi transit. KM11060 is a potentially useful substance for the advancement of CF treatments. [1]
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| ln Vivo |
When LPS causes acute lung inflammation, plasma lipoxin A4 levels in F508del mice relative to wildtype mice can be markedly elevated by blocking PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, blocking PAF by WEB2086, or correcting mutated CFTR trafficking by KM11060. [2]
CFTR (cystic fibrosis transmembrane conductance regulator) is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del) or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2) or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage) during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF) levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase) inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.[2] |
| Enzyme Assay |
KM11060 is a novel corrector of the F508del-CFTR (cystic fibrosis transmembrane conductance regulator) trafficking defect. It corrects F508del-CFTR trafficking, and increases the amount of functional CFTR at the plasma membrane (~75%) and inhibits PDE5 activity.
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| Cell Assay |
Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics. KM11060 rescues F508del-CFTR trafficking in cultured cells and native epithelial tissues. KM11060 partially corrects F508del-CFTR processing and increases surface expression to 75% of that observed in cells incubated at low temperature. Up to 50% of the F508del-CFTR in cells treated with KM11060 was complex-glycosylated, indicating passage through the Golgi. KM11060 as a promising compound for further development of CF therapeutics.
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| Animal Protocol |
Administration of CFTR Inhibitors[2]
Mice were intraperitoneally injected (ip) with MalH-2 (dissolved in PBS, 3 mg/kg) or CFTRinh-172 (dissolved in DMSO, 3 mg/kg) 15∼20 min before intratracheal challenge with E. coli or LPS to establish lung inflammation mouse models. E. coli Pneumonia and LPS-induced Acute Lung Inflammation Models[2] Eight to ten-week old CD1 wild-type and CF mice (targeted F508del gene replacement, obtained from Professor A. Verkman, University of California San Francisco) were used for these studies. Anesthesia was induced with an ip injection of a mixture of ketamine (90 mg/kg) and xylazine (10 mg/kg). [2] A previously developed direct visualization instillation (DVI) method was used to instill LPS into the airspaces of the lung. The LPS dosage (5 mg/kg) was selected aiming to induce a robust lung inflammation and injury at 24 h as previously reported and no mice died at this dosage. For establishing E. coli pneumonia, 107 cfu of E. coli were instilled into the airspaces of the lung as reported before. E. coli pneumonia and LPS-induced acute lung inflammation mouse models were followed for 4 and 24 respectively. Vital signs of each mouse were observed timely. At the end of experiment, mice were first anesthetized and then sacrificed by cervical dislocation. |
| References |
[1]. Robert R, et al. Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol. 2008 Feb;73(2):478-89.
[2]. Wu H, et al. Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice. PLoS One. 2014 Mar 26;9(3):e93003. |
| Additional Infomation |
The F508del mutation impairs trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) to the plasma membrane and results in a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We recently used a novel high-throughput screening (HTS) assay to identify small-molecule correctors of F508del CFTR trafficking and found several classes of hits in a screen of 2000 compounds (Carlile et al., 2007). In the present study, we have extended the screen to 42,000 compounds and confirmed sildenafil as a corrector using this assay. We evaluated structural analogs of sildenafil and found that one such molecule called KM11060 (7-chloro-4-{4-[(4-chlorophenyl) sulfonyl] piperazino}quinoline) was surprisingly potent. It partially restored F508del trafficking and increased maturation significantly when baby hamster kidney (BHK) cells were treated with 10 nM for 24 h or 10 muM for 2 h. Partial correction was confirmed by the appearance of mature CFTR in Western blots and by using halide flux, patch-clamp, and short-circuit current measurements in unpolarized BHK cells, monolayers of human airway epithelial cells (CFBE41o(-)), and intestines isolated from F508del-CFTR mice (Cftr(tm1Eur)) treated ex vivo. Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics.[1]
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| Molecular Formula |
C19H17CL2N3O2S
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| Molecular Weight |
422.33
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| Exact Mass |
421.0419
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| Elemental Analysis |
C, 54.04; H, 4.06; Cl, 16.79; N, 9.95; O, 7.58; S, 7.59
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| CAS # |
774549-97-2
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| Related CAS # |
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| PubChem CID |
1241327
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
607.3±65.0 °C at 760 mmHg
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| Flash Point |
321.1±34.3 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.676
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| LogP |
4.2
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| tPSA |
61.89
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| SMILES |
O=S(N1CCN(C2=CC=NC3=CC(Cl)=CC=C23)CC1)(C4=CC=C(Cl)C=C4)=O
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| InChi Key |
GIEHIZKCIZLXLF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17Cl2N3O2S/c20-14-1-4-16(5-2-14)27(25,26)24-11-9-23(10-12-24)19-7-8-22-18-13-15(21)3-6-17(18)19/h1-8,13H,9-12H2
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| Chemical Name |
7-chloro-4-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)quinoline
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| Synonyms |
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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) |
DMSO: ~84 mg/mL ( 198.89 mM）
Water: Insoluble Ethanol: <2 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.84 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 10%DMSO+90%corn oil：≥ 5 mg/mL (11.84 mM); Clear solution (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3678 mL | 11.8391 mL | 23.6782 mL | |
| 5 mM | 0.4736 mL | 2.3678 mL | 4.7356 mL | |
| 10 mM | 0.2368 mL | 1.1839 mL | 2.3678 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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