Losmapimod hydrochloride
Based on 12 publication(s) in Google Scholar
Losmapimod (GSK-AHAB; GW856553X) hydrochloride is an orally active p38α/β MAPK inhibitor, with pKi values of 8.1 and 7.6 for p38α and p38β, respectively. Losmapimod hydrochloride reduces DUX4 expression, thus exerting efficacy in facioscapulohumeral muscular dystrophy. By inhibiting MAPK/NF-κB, Losmapimod hydrochloride reduces apoptosis of epileptiform hippocampal neurons, and exhibits anti-allodynia and anti-hyperalgesic activities. Losmapimod hydrochloride blocks the entry and fusion of Lassa fever virus (LASV). Losmapimod hydrochloride overcomes tyrosine kinase inhibitor resistance in non-small cell lung cancer (NSCLC). Losmapimod hydrochloride inhibits myocardial senescence and inflammation, and possesses cardioprotective activity against cardiotoxicity.
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- CAS No.: 1246654-84-1
- Formule: C22H27ClFN3O2
- Masse moléculaire:419.92
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Publications Citing Use of MedChemExpress (MCE) Losmapimod hydrochloride
More- J Exp Clin Cancer Res. 2023 Jul 13;42(1):166. [Abstract]
- EBioMedicine. 2018 Feb:28:51-61. [Abstract]
- Cell Commun Signal. 2025 Jan 8;23(1):14. [Abstract]
- EMBO Mol Med. 2023 Mar 8;15(3):e16235. [Abstract]
- Cell Syst. 2018 Apr 25;6(4):424-443.e7. [Abstract]
- Cell Mol Life Sci. 2022 Aug 5;79(8):467. [Abstract]
- J Cell Mol Med. 2023 Sep;27(17):2583-2593. [Abstract]
- Neurochem Int. 2015 Nov;90:1-8. [Abstract]
- Aging (Albany NY). 2021 Aug 10;13(15):19088-19107. [Abstract]
- Am J Physiol Lung Cell Mol Physiol. 2012 Nov 15;303(10):L929-38. [Abstract]
- Leuk Lymphoma. 2021 Dec;62(14):3361-3372. [Abstract]
- Patent. US20180296546A1.
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Activité biologique
Losmapimod (0.1-10 μM; 48.25 h) hydrochloride potently inhibits LASV-GP (strain Josiah)/HIV-luc pseudovirus infection in HEK293T cells with an EC50 of 3.68 μM[2].
Losmapimod (0.02-50 μM; 73 h) hydrochloride effectively inhibits authentic LASV (strain Josiah) infection in Vero E6 cells, with EC50 values of 2.18 μM (TCID50) and 0.71 μM (RT-qPCR)[2].
Losmapimod (30 μM; 48.25 h) hydrochloride inhibits infection by LASV-GP/HIV-luc pseudoviruses from four distinct LASV lineages in HEK293T cells, with EC50 values ranging from 0.9 μM to 2.7 μM[2].
Losmapimod (30 μM) hydrochloride blocks LASV-GP (strain Josiah)/HIV-luc pseudovirus infection in U-87 MG cells exclusively at the post-attachment viral fusion step[2].
Losmapimod (10 μM) hydrochloride specifically inhibits low pH-triggered LASV-GP (strain Josiah) mediated cell-cell fusion in HEK293T cells when added prior to pH exposure[2].
Losmapimod (3-30 μM) hydrochloride dose-dependently inhibits LASV-GP (strain Josiah) mediated cell-cell fusion in co-cultured HEK293T and U-87 MG cells, with significant inhibition observed at concentrations as low as 3 μM[2].
Losmapimod (0.3-30 μM; 48.25 h) hydrochloride inhibits LASV-GP (strain Josiah)/HIV-luc pseudovirus infection in HEK293T cells by targeting the SSP-GP2 interface, as it is ineffective against pseudoviruses with LASV SSP and transmembrane domains replaced by LCMV sequences[2].
Losmapimod (1 μM; 24 h) hydrochloride eliminates gefitinib-induced tetraploidization in Gefitinib (HY-50895)-resistant HCC827GR and H1975 human lung adenocarcinoma cells when used in combination with 1 μM gefitinib[4].
Losmapimod (1 μM; 10-24 h) hydrochloride inhibits gefitinib-induced activation of the p38 MAPK-STAT3 pathway and subsequent up-regulation of p21 and cyclin D1 in Gefitinib-resistant HCC827GR and H1975 human lung adenocarcinoma cells when used in combination with 1 μM gefitinib[4].
Losmapimod (1 μM; 3 weeks) hydrochloride in combination with 1 μM Gefitinib significantly inhibits anchorage-independent growth of gefitinib-resistant HCC827GR and H1975 human lung adenocarcinoma cells[4].
Losmapimod (1 μM; 72 h) hydrochloride in combination with 1 μM gefitinib synergistically reduces viability of Gefitinib-resistant HCC827GR (combination index 0.14) and H1975 (combination index 0.22) human lung adenocarcinoma cells[4].
Losmapimod (1 μM; 3 h) hydrochloride reduces apoptosis, inhibits MAPK/NF-κB signaling activation, and suppresses inflammatory factor production in epileptiform human hippocampal neurons, with no harmful effects on normal human hippocampal neurons[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:gefitinib-resistant HCC827GR and H1975 human lung adenocarcinoma cells
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Concentration:1 μM (in combination with 1 μM Gefitinib)
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Incubation Time:24 h
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Result:Eliminated gefitinib-induced tetraploidization, as measured by the disappearance of the tetraploid (G1) cell subpopulation in flow cytometry analysis.
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Cell Line:gefitinib-resistant HCC827GR and H1975 human lung adenocarcinoma cells
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Concentration:1 μM (either alone or in combination with 1 μM Gefitinib)
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Incubation Time:2 h, 6 h, 10 h, 24 h
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Result:Inhibited gefitinib-induced phosphorylation of p38 MAPK at 10 h in both cell lines.
Did not alter gefitinib-induced phosphorylation of YAP at 2 h or MKK3/6 at 6 h, and further up-regulated gefitinib-induced MKK3/6 phosphorylation.
Inhibited gefitinib-induced phosphorylation of STAT3 at 10 h, as well as gefitinib-induced up-regulation of p21 at 10 h and cyclin D1 at 24 h in both cell lines.
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Cell Line:gefitinib-resistant HCC827GR and H1975 human lung adenocarcinoma cells
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Concentration:1 μM (in combination with 1 μM gefitinib)
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Incubation Time:72 h
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Result:Reduced cell viability to approximately 75% in HCC827GR cells and approximately 70% in H1975 cells, while losmapimod or gefitinib alone had no inhibitory effect.
Synergistically inhibited cell proliferation with a combination index of 0.14 for HCC827GR cells and 0.22 for H1975 cells.
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Cell Line:human hippocampal neurons
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Concentration:1 μM
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Incubation Time:3 h
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Result:Reduced the apoptosis rate of epileptiform human hippocampal neurons from ~17% to ~8%.
Reversed the upregulation of Bax and cleaved caspase 3, and the downregulation of Bcl-2 in epileptiform neurons.
Inhibited the increased phosphorylation of p38 and IκB, and restored reduced IκB expression in epileptiform neurons.
Suppressed the elevated levels of TNF-α, IL-1β, IL-6, IL-10, and CRP in epileptiform neurons.
Showed no significant effect on normal neurons.
Losmapimod (1.8 mg/kg; i.p.; once daily; 3 days) hydrochloride protects against Pilocarpine (HY-B0726A)-induced epilepsy in Sprague-Dawley rats by inhibiting MAPK/NF-κB pathway activation, reducing neuronal apoptosis and inflammation, restoring synaptic receptor expression, improving seizure parameters, and reversing cognitive deficits[5].
Losmapimod (2-50 mg/kg; p.o.; once daily; Day 0 to Day 2) hydrochloride produces dose-dependent antiallodynic and antihyperalgesic effects in Carrageenan-induced acute pain, with an ED50 of 6.8 mg/kg for mechanical allodynia and 3.4 mg/kg for thermal hyperalgesia, and inhibits early neuronal and microglial p38 activation[6].
Losmapimod (30 mg/kg; p.o.; once daily; Day 0 to Day 2) hydrochloride provides significant antinociceptive effects in plantar incision-induced postoperative pain[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6N (male, 4 weeks old, acclimated for 1 week prior to study, chronic doxorubicin-induced cardiotoxicity model)[3]
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Dosage:12 mg/kg/day
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Administration:p.o.; continuous; 4 days pre-doxorubicin plus 6-week doxorubicin treatment period
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Result:Attenuated doxorubicin-induced reduction in left ventricular ejection fraction, fractional shortening, and heart rate.
Mitigated doxorubicin-induced upregulation of cardiac Nppb (brain natriuretic peptide) gene expression.
Abrogated doxorubicin-induced upregulation of the senescence marker p21^Cip1 in both heart and liver tissue.
Reduced doxorubicin-induced upregulation of cardiac Il-1α and Il-6 gene expression.
Decreased serum IL-6 and CXCL1 levels in both saline- and doxorubicin-treated mice compared to control diet groups.
Significantly upregulated cardiac mitofusin2 (Mfn2) gene expression in both saline- and doxorubicin-treated mice.
Attenuated p38 MAPK activation in both heart and liver tissue of saline- and doxorubicin-treated mice.
Increased JNK activation in heart and liver tissue of saline-treated mice; doxorubicin reduced this effect in the liver but not the heart.
No significant effect on doxorubicin-induced cardiac atrophy (heart weight/tibia length ratio).
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Animal Model:Sprague-Dawley (adult male, 6-8 weeks old, 180-220 g, epilepsy induced by subcutaneous methylscopolamine pre-treatment followed by intraperitoneal pilocarpine injections to induce status epilepticus)[5]
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Dosage:1.8 mg/kg
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Administration:i.p.; once daily; 3 days
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Result:Increased Nissl-positive cell count in the hippocampal CA3 region from ~170 to ~230.
Decreased hippocampal neuron apoptosis rate from ~17% to ~10%.
Reversed SE-induced upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2.
Reduced SE-induced increases in p-p38 and p-IκB protein expression, and restored IκB protein levels.
Reduced SE-induced upregulation of IL-6, TNF-α, IL-1β, IL-10, and CRP in hippocampal tissue.
Partly reversed SE-induced upregulation of NMDAR subunits (NR1A, NR2A, NR2B, NR2C, NR2D) and AMPAR GRIA2 subunit gene expression.
Increased incubation period of clonic cramp to 92.8 s, transition time to 40.1 s, and incubation period of tetanic convulsion to 126.9 s.
Reduced rate of tetanic convulsions from ~100% to ~65%.
Reduced mean escape latency and mean path length in the Morris water maze.
Increased time spent in the target quadrant and number of platform crossings compared to SE alone rats.
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Animal Model:Sprague-Dawley (male, 280-300 g, acute pain model via 3% carrageenan subcutaneous injection in left hind paw)[6]
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Dosage:2 mg/kg; 4 mg/kg; 12 mg/kg; 50 mg/kg
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Administration:p.o.; once daily; Day 0 to Day 2
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Result:Reversed carrageenan-induced mechanical allodynia and thermal hyperalgesia with efficacy similar to morphine at 12 mg/kg.
Reached an ED64 for mechanical allodynia and ED78 for thermal hyperalgesia at 12 mg/kg.
Yielded an ED50 of 6.8 mg/kg for mechanical allodynia and 3.4 mg/kg for thermal hyperalgesia from dose-response curve.
Significantly increased paw withdrawal thresholds to mechanical and thermal stimulation compared to baseline.
Reduced the percentage of activated p-p38-expressing DRG neurones from 90% to 50% at 2 hours after carrageenan injection.
Reduced the number of activated p-p38-expressing ipsilateral spinal cord microglial cells from 43 to 20 at 15 hours after carrageenan injection.
Showed no effect on astrocytic activation at any time point.
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Animal Model:Sprague-Dawley (male, 280-300 g, postoperative pain model via plantar incision)[6]
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Dosage:30 mg/kg
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Administration:p.o.; once daily; Day 0 to Day 2
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Result:Significantly reversed plantar incision-induced allodynia and hyperalgesia, enhancing paw withdrawal thresholds compared to incision-only controls.
Chemical Information
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CAS No. 1246654-84-1
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Masse moléculaire 419.92
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Formule C22H27ClFN3O2
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SMILES
O=C(C1=CN=C(C2=C(C)C(F)=CC(C(NC3CC3)=O)=C2)C=C1)NCC(C)(C)C.Cl
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Synonyms
GSK-AHAB hydrochloride; GW856553X hydrochloride; SB856553 hydrochloride
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Publications (12)
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Journal Impact Factor
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Most Recent
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J Exp Clin Cancer Res
Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation. [Abstract]2023 Jul 13;42(1):166. PMID: 37443052 -
EBioMedicine
Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. [Abstract]2018 Feb:28:51-61. PMID: 29398601
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Western blot analysis of p-YAP, p-MKK3/6 and p-p38 expressions in untreated ZD1839-resistant cells (left, HCC827GR and right, H1975) or cells treated for 2, 6 or 10 h with ZD1839 (1 μM) or Losmapimod (1 μM) either alone or in combination. Total YAP, MKK3/6 and p38 MAPK proteins are used as loading controls.
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Losmapimod (1 μM; 24 h) could eliminate gefitinib-induced tetraploidy in both resistant cell lines (left, HCC827GR and right, H1975).
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Losmapimod (1 μM; 24 h) phosphorylation of STAT3 and expressions of p21 and cyclin D1 were up-regulated with gefitinib treatment in both resistant cell lines, and that the up-regulations could be inhibited by losmapimod (left, HCC827GR and right, H1975).
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Losmapimod (72 h) did not inhibit cell viability in HCC827GR and H1975 cells.
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Losmapimod (12 mg/kg; daily; PO; for 15 days) alone or in combination with gefitinib markedly reduced gefitinib-resistant NSCLC PDX tumor volume and weight; no changes in mouse body weight were observed.
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EBioMedicine. 2018 Feb:28:51-61. [Abstract]
Losmapimod (12 mg/kg; daily; PO; for 15 days) significantly reduced cyclin D1, p-p38 and Ki-67 expression in xenograft tissues.
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Cell Commun Signal
Staphylococcus aureus vesicles impair cutaneous wound healing through p38 MAPK-MerTK cleavage-mediated inhibition of macrophage efferocytosis. [Abstract]2025 Jan 8;23(1):14. PMID: 39780180 -
EMBO Mol Med
Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance. [Abstract]2023 Mar 8;15(3):e16235. PMID: 36652375
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: EMBO Mol Med. 2023 Mar 8;15(3):e16235. [Abstract]
Losmapimod (10 μM) inhibited p38 activity and prevented thiaparib-induced p‐STAT1 in JeKo‐1 and THP‐1 cells.
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Cell Syst
A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations. [Abstract]2018 Apr 25;6(4):424-443.e7. PMID: 29655704 -
Cell Mol Life Sci
Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse. [Abstract]2022 Aug 5;79(8):467. PMID: 35930080 -
J Cell Mol Med
Phosphorylated MAPK11 promotes the progression of clear cell renal cell carcinoma by maintaining RUNX2 protein abundance. [Abstract]2023 Sep;27(17):2583-2593. PMID: 37525479 -
Neurochem Int
Suppression of mitochondrial fission in experimental cerebral ischemia: The potential neuroprotective target of p38 MAPK inhibition. [Abstract]2015 Nov;90:1-8. PMID: 26116440
Losmapimod hydrochloride purchased from MedChemExpress. Usage Cited in: Neurochem Int. 2015 Nov;90:1-8. [Abstract]
Inhibition of p38 MAPK (p38 inhibitor, Losmapimod 1 mg/kg) suppressed DLP1 and MFF with the temporal-accumulated effect after ischemia-reperfusion.
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Aging (Albany NY)
2021 Aug 10;13(15):19088-19107. PMID: 34375950 -
Am J Physiol Lung Cell Mol Physiol
Cigarette smoke and its component acrolein augment IL-8/CXCL8 mRNA stability via p38 MAPK/MK2 signaling in human pulmonary cells. [Abstract]2012 Nov 15;303(10):L929-38. PMID: 22983351 -
Leuk Lymphoma
2021 Dec;62(14):3361-3372. PMID: 34355652 -
Pureté et documentation
Références
[1].
Tawil R, et al. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2024 May;23(5):477-486.
[Content Brief]
[2]. Zhang X, et al. Identification of a clinical compound losmapimod that blocks Lassa virus entry. Antiviral research. 2019 Jul;167:68-77. [Content Brief]
[3]. Dabour MS, et al. Losmapimod ameliorates doxorubicin-induced cardiotoxicity through attenuating senescence and inflammatory pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2024 Oct;179:117288. [Content Brief]
[4]. Yeung YT, et al. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. EBioMedicine. 2018 Feb;28:51-61. [Content Brief]
[5]. Li M, et al. Losmapimod Protected Epileptic Rats From Hippocampal Neuron Damage Through Inhibition of the MAPK Pathway. Frontiers in pharmacology. 2019;10:625. [Content Brief]
[6].
Soued M, et al. Antinociceptive properties of losmapimod in two acute pain models in rats: behavioural analysis, immunohistochemistry, dose response, and comparison with usual analgesic drugs. BJA Open. 2022 Aug 17;3:100029.
[Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Losmapimod hydrochloride Related Classifications
HY-10402A Related Classifications
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