BIM-46174
BIM-46174 is a heterotrimeric G protein complex inhibitor. BIM-46174 blocks GPCR downstream signaling by trapping Gα proteins in a nucleotide-free pocket conformation, thereby inhibiting Gαq-mediated calcium release, Gαs-mediated cAMP production, and GPCR-regulated cancer cell invasion. In vitro, BIM-46174 effectively suppresses a variety of clinically multidrug-resistant cell lines and induces tumor cell apoptosis through activation of caspase-3 and PARP cleavage. BIM-46174 also inhibits activation of the Neu1-MMP-9-GPCR signaling platform and downstream NF-κB signaling, and is widely used in the study of cancer signaling pathways and inflammation-related research, including lung cancer, pancreatic cancer, breast cancer, melanoma, and leukemia.
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- CAS. Nr.: 195450-11-4
- Formel: C22H30N4OS
- Molecular Weight:398.56
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Biologische Aktivität
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NTR1 0.7 μM (IC50) |
MMP-9 |
MMP-3 |
TLR7 7.94 μM (IC50) |
TLR9 20 μM (IC50) |
Wnt2 |
Caspase 3 |
BIM-46174 (1-100 μM; 1 h) in human breast cancer MCF-7 cells, as a heterotrimeric G protein inhibitor, significantly and reversibly blocks cAMP pathway activation mediated by cholera toxin or vasoactive intestinal peptide[1].
BIM-46174 (5-30 μM; 1-24 h) selectively inhibits endothelin-1-coupled intracellular Ca2+ release in melanoma A2058 cells and markedly reverses or abolishes Wnt-2/3a- or neurotensin-induced invasive activity in colorectal cancer HCT8/S11, lung cancer LNM35, and colon cancer HT29 cells (IC50 = 0.7 μM)[1].
BIM-46174 (0.6-30 μM; 72-96 h) exhibits potent in vitro antiproliferative activity across a broad spectrum of human cancer cell lines, with IC50 values ranging from 0.6 to 25 μM, effectively suppresses multiple clinical multidrug-resistant cell lines, and induces apoptosis via Caspase-3 activation and PARP cleavage[1].
BIM-46174 (10-200 μM; 30 min-24 h) in macrophages (RAW-blue/RAW264.7) markedly blocks upstream G protein signaling, thereby inhibiting lmiquimod (HY-B0180)- or nucleic acid-induced TLR7/9 activation and MyD88 adaptor recruitment, resulting in suppression of NF-κB phosphorylation and pro-inflammatory cytokine (TNFα, MCP-1/CCL2) release[2].
BIM-46174 (10-30 μM; 1-30 min) in 3T3-hEGFR cells and human pancreatic cancer cells (PANC-1/MiaPaCa-2) inhibits post-receptor Neu1 sialidase activation induced by epidermal growth factor (EGF) via blockade of upstream G protein signaling, thereby preventing downstream epidermal growth factor receptor (EGFR) autophosphorylation[3].
BIM-46174 (100 μM; 2 h) in human embryonic kidney HEK293 cells strongly inhibits Gαq-dependent intracellular accumulation of the second messenger myo-inositol 1-phosphate (IP1) induced by Carbachol (HY-B1208)[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:A-427, PC3, HL60, CCRF-CEM, MIA PaCa-2, NCI-H69, U-87MG, A2058, HT29, and DU145 cells
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Concentration:0.6-25 μM
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Incubation Time:96 h
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Result:Inhibited the in vitro proliferation of a large panel of human cancer cell lines, including various anticancer drug-resistant variants, with significantly lower resistance factors than reference drugs.
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Cell Line:HL60 and NCI-H69 cells
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Concentration:30 μM
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Incubation Time:72 h
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Result:Resulted in a significant 5-fold increase in apoptosis and induced caspase-3 activation along with cleaved PARP appearance.
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Cell Line:HCT8/S11, LNM35, HT29, and MDCKts.src cells
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Concentration:5 μM
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Incubation Time:24h
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Result:Abrogated or completely reversed the invasive potential induced by Wnt-2, Wnt-3a, neurotensin, or aluminium fluoride, but showed no effect on invasion induced by constitutively activated Gα12, Gα13, or Gβ1γ2 dimers.
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Cell Line:RAW-blue and RAW264.7 macrophage cells
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Concentration:20 μM
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Incubation Time:30 min
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Result:Inhibited imiquimod- and ODN-induced NF-κB pSer536 activation in the cytoplasmic cell lysates.
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Cell Line:3T3-hEGFR cells
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Concentration:20 μM
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Incubation Time:30 min
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Result:Inhibited EGF-induced EGFR tyrosine kinase receptor phosphorylation in cell lysates.
BIM-46174 (25 mg/kg; i.p.; twice daily for 8 days) in a human non-small cell lung cancer LNM35 xenograft model significantly reduces tumor growth when combined with Cisplatin (HY-17394) (1 mg/kg, once daily for 5 days) and exhibits good tolerability with low systemic toxicity[1].
BIM-46174 (20 mg/kg; i.p.; twice daily for 5 days) in a human pancreatic cancer MIA PaCa-2 xenograft model significantly delays tumor growth and exhibits synergistic antitumor activity when combined with the topoisomerase inhibitor (HY-13622) while maintaining a favorable safety profile throughout the whole period[1].
BIM-46174 (2 mg/kg/h; continuous intravenous infusion; 6 days) in a rat continuous infusion toxicity model is established as the highest tolerated dose before significant body weight loss, with no marked abnormalities in key biochemical parameters[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCLC NCI-H69 tumor xenograft model (Female athymic NCr-nu/nu mice, 4-6 weeks)[1]
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Dosage:20 or 25 mg/kg
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Administration:Intraperitoneal injection (i.p.); 25 mg/kg twice daily for 14 days, or 20 mg/kg twice daily for 5 days
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Result:Showed that administered alone at 25 mg/kg or 20 mg/kg resulted in minimal tumor growth inhibition.
Demonstrated that combined treatment with Cisplatin (HY-17394) (1.5 mg/kg for 5 consecutive days) induced a drastic and significant reduction of the tumor growth rate.
Revealed that combination therapy with the farnesyltransferase inhibitor produced significant antitumor activity.
Observed a limited and acceptable body weight loss across all combination treatment groups, indicating minimal systemic toxicity.
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Animal Model:NSCLC LNM35 tumor xenograft model (Female athymic NCr-nu/nu mice, 4-6 weeks)[1]
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Dosage:25 mg/kg
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Administration:Intraperitoneal injection (i.p.); twice daily for 8 days
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Result:Demonstrated that combined treatment with Cisplatin (HY-17394) (1 mg/kg for 5 consecutive days) achieved a drastic and statistically significant reduction in the tumor growth rate compared to the vehicle or single-agent groups.
Associated with minimal toxicity, presenting only a limited and acceptable body weight loss in the treated animals.
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Animal Model:Pancreatic cancer MIA PaCa-2 tumor xenograft model (Female athymic NCr-nu/nu mice, 4-6 weeks)[1]
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Dosage:20 mg/kg
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Administration:Intraperitoneal injection (i.p.); twice daily for 5 days
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Result:Revealed that combination therapy with the topoisomerase inhibitor (HY-13622) (2 mg/kg twice daily for a 14-day cycle) induced a profound and highly significant delay in the pancreatic tumor growth rate.
Maintained a safe safety profile with minimal toxicity and limited body weight loss observed throughout the regimen.
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Animal Model:Continuous infusion toxicity evaluation in rats[1]
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Dosage:2 mg/kg/h
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Administration:Continuous intravenous infusion for 6 days
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Result:Established this regimen as the highest tolerable dose before triggering significant body weight loss after 6 days of continuous delivery.
Showed no significant pathopharmacological changes in key biochemical blood markers, including urea, creatinine, glycemia, γ-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase, indicating no significant liver or kidney dysfunction.
Chemical Information
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CAS. Nr. 195450-11-4
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Molecular Weight 398.56
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Formel C22H30N4OS
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SMILES
SC[C@H](N)C(N1CCN2C([C@@H]1CC3CCCCC3)=NC(C4=CC=CC=C4)=C2)=O
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Prévost GP, et al. Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex. Cancer Res. 2006 Sep 15;66(18):9227-34. [Content Brief]
[2]. Abdulkhalek S, et al. Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and -9 activation, cellular signaling and pro-inflammatory responses. Cell Signal. 2013 Nov;25(11):2093-105. [Content Brief]
[3]. Gilmour AM, et al. A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer. Cell Signal. 2013 Dec;25(12):2587-603. [Content Brief]
[4]. Küppers J, et al. Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as Gαq -Protein Ligands. Chemistry. 2020 Oct 1;26(55):12615-12623. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
BIM-46174 Related Classifications
HY-183400 Related Classifications
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- BIM-46174
- 195450-11-4
- BIM46174
- BIM 46174
- Neurotensin Receptor
- MMP
- EGFR
- Toll-like Receptor (TLR)
- Wnt
- Caspase
- PARP
- MyD88
- NF-κB
- TNF Receptor
- Apoptosis
- G protein inhibitor
- GPCR signaling
- Toll-like Receptor
- EGFR signaling
- apoptosis
- HL60 cells
- RAW 264.7 cells
- MCF-7 cells
- A2058 cells
- MIA PaCa-2 cells
- RAG2/Cy double mutant mice
- athymic nude mice
- xenograft model
- lung cancer
- pancreatic cancer
- breast cancer
- Inhibitor
- inhibitor
- inhibit