KCN1
KCN1 is a p300/HIF-1α interaction inhibitor with a Kd value of 345 nM for p300-CH1. KCN1 binds to the CH1 domain of p300, blocks the assembly of the p300/HIF-1α complex, and disrupts the HIF-1α-p300/CBP interaction. KCN1 inhibits cancer cell growth, induces cancer cell cycle arrest and apoptosis. KCN1 inhibits β-galactosidase activity and downregulates the expression of VEGF, Glut1, CA9 and CAIX. KCN1 exerts anticancer activity in mouse tumor xenograft models. KCN1 can be used in research related to malignant glioma, pancreatic cancer and metastatic uveal melanoma.
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- No. CAS: 927823-01-6
- Fòrmula: C26H27NO5S
- Peso molecular:465.56
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Actividad biológica
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p300-CH1 345 nM (Kd) |
GLUT1 |
CA IX |
CA9 |
KCN1 (3-60 μg/mL p300-CH1) binds to recombinant p300-CH1 peptide in SPR assays, with a KD value of approximately 345 nM[1].
KCN1 (1-100 μM; 72 h) inhibits the viability of human pancreatic cancer cell lines HPAC, Panc-1, BxPC3 and Mia Paca-2 in vitro in a dose-dependent manner, with IC50 values ranging from 14.62 μM (BxPC3) to 99.99 μM (Panc-1)[2].
KCN1 (5-50 μM; 24 h) inhibits the proliferation of human pancreatic cancer cells HPAC, Panc-1, BxPC3 and Mia Paca-2 in vitro in a dose-dependent manner, and the proliferation rate decreases by 56-88% at the concentration of 50 μM[2].
KCN1 (5-50 μM; 14 days) dose-dependently inhibits the anchorage-independent growth of human pancreatic cancer cells HPAC and Panc-1 in vitro, and reduces their colony-forming ability by 3-4 folds at the concentration of 50 μM[2].
KCN1 (1-15 μM; under hypoxia following 1 h normoxic pre-treatment) specifically inhibits HRE-dependent hypoxia-induced luciferase activity in LN229HRE-luc/lacZ human glioblastoma cells, with an IC50 of approximately 593 nM[3].
KCN1 (10 μM; administered under hypoxia following 1 h of normoxic pre-treatment) inhibits hypoxia-induced β-galactosidase activity in LN229HRE-luc/lacZ human glioblastoma cells, without affecting constitutive CMV-driven β-galactosidase activity[3].
KCN1 (10 μM; 24 h under hypoxia following 1 h pre-treatment) inhibits HRE-dependent hypoxia-induced luciferase activity in U251MG, D54MG, D645MG and LN443 human glioblastoma cell lines, exhibiting broad activity against genetically diverse gliomas[3].
KCN1 (10 μM; 24 h under hypoxia following 1 h pre-treatment) specifically inhibits HRE-dependent transcription in human glioblastoma LN229 cells, without affecting the transcriptional activities mediated by NF-κB, AP1 or p53[3].
KCN1 (25 μM; 4-24 h under normoxia or hypoxia) downregulates hypoxia-induced VEGF and Glut1 mRNA expression in LN229 human glioblastoma cells without altering constitutive β-actin mRNA levels[3].
KCN1 (25 μM; under normoxia or hypoxia) downregulates hypoxia-induced CA9 mRNA expression in U251MG human glioblastoma cells without altering constitutive β-actin mRNA levels[3].
KCN1 (10 μM; 48 h under normoxia or hypoxia) inhibits hypoxia-induced VEGF protein secretion in LN229 human glioblastoma cells under normoxic or hypoxic conditions[3].
KCN1 (10 μM; 24 h under hypoxia following 1 h pre-treatment) inhibits hypoxia-induced promoter activities of wild-type VEGF and CA9 in human glioblastoma LN229 cells, but exerts no effect on the promoter activities of HRE-mutated VEGF and CA9, confirming that its action is dependent on HRE[3].
KCN1 (10 μM; under normoxia or hypoxia) downregulates hypoxia-induced CAIX protein expression in LN229 human glioblastoma cells without altering constitutive Akt protein levels[3].
KCN1 (2.5-10 μM; incubated with nuclear extracts and HRE oligonucleotide) reduces the recruitment of p300 to HRE-bound HIF-1α in nuclear extracts of LN229 human glioblastoma under hypoxic conditions, without affecting the binding of HIF-1α to HRE[3].
KCN1 (10 μM; 24 h under hypoxia following 1 h pre-treatment) reduces the recruitment of p300 and CBP by endogenous CA9 HRE in LN229 human glioblastoma cells under hypoxic conditions, without affecting the binding of HIF-1α to CA9 HRE[3].
KCN1 (5-50 μM; 48 h) induces mild apoptosis in HPAC human pancreatic cancer cells in vitro, whereas no apoptosis is detected in Panc-1, BxPC3 or Mia Paca-2 cells even at concentrations up to 50 μM[2].
KCN1 (5-50 μM; 24 h) induces G1 phase cell cycle arrest in human pancreatic cancer cell lines HPAC, Panc-1, BxPC3 and Mia Paca-2 in a dose-dependent manner in vitro, with significant effects starting at concentrations of 5 μM (HPAC, BxPC3, Mia Paca-2) or 12.5 μM (Panc-1)[2].
KCN1 (5-50 μM; 12-24 h) regulates the expression of cell cycle-related proteins in human pancreatic cancer cell lines HPAC, Panc-1, BxPC3 and Mia Paca-2 in vitro, reduces the levels of pro-proliferative regulatory factors and increases the levels of cyclin-dependent kinase inhibitors[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HPAC, Panc-1, BxPC3, Mia Paca-2
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Concentration:0, 1, 5, 12.5, 25, 50, 100 μM
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Incubation Time:72 h
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Result:Inhibited cell growth in a dose-dependent manner.
Reduced cell viability by 83% in HPAC, 53% in Panc-1, 81% in BxPC3, and 61% in Mia Paca-2 cells at 100 μM.
Exhibited IC50 values of 17.91 μM for HPAC, 99.99 μM for Panc-1, 14.62 μM for BxPC3, and 69.91 μM for Mia Paca-2 cells.
Showed time-course sensitivity ranking as BxPC3 > HPAC > Mia Paca-2 > Panc-1.
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Cell Line:HPAC, Panc-1, BxPC3, Mia Paca-2
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Concentration:0, 5, 12.5, 50 μM
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Incubation Time:24 h
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Result:Inhibited cell proliferation in a dose-dependent manner across all four cell lines.
Reduced proliferation by 80% in HPAC, 56% in Panc-1, 88% in BxPC3, and 60% in Mia Paca-2 cells at 50 μM.
Showed BxPC3 cells as the most sensitive at the highest concentration.
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Cell Line:HPAC, Panc-1, BxPC3, Mia Paca-2
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Concentration:0, 5, 12.5, 50 μM
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Incubation Time:48 h
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Result:Showed negligible or weak apoptotic effects across all four cell lines.
Induced a 1.4-fold increase in the apoptotic index in HPAC cells at 50 μM.
Caused no detectable apoptotic activity in Panc-1, BxPC3, or Mia Paca-2 cells.
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Cell Line:HPAC, Panc-1, BxPC3, Mia Paca-2
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Concentration:0, 5, 12.5, 50 μM
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Incubation Time:24 h
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Result:Induced dose-dependent G1 phase cell cycle arrest in all four cell lines.
Triggered significant arrest starting at 5 μM in HPAC (P<0.01), BxPC3 (P<0.01), and Mia Paca-2 (P<0.01) cells, and at 12.5 μM in Panc-1 (P<0.01) cells.
Increased G1 phase percentages to 68.8% (HPAC), 53.3% (Panc-1), 70.8% (BxPC3), and 58.9% (Mia Paca-2) at 50 μM, compared to control values of 39.4%, 39.5%, 45.1%, and 46.7%, respectively.
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Cell Line:HPAC, Panc-1, BxPC3, Mia Paca-2
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Concentration:0, 5, 12.5, 50 μM
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Incubation Time:12 h, 24 h
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Result:Decreased expression of cell cycle regulators E2F1, Cdk2, Cdk4, Cdk6, Cdc25c, Cyclin D1, and Cyclin E in all four cell lines.
Increased expression of p21 and p27 in all four cell lines, regardless of incubation duration.
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Cell Line:LN229 human glioblastoma cells
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Concentration:10 μM
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Incubation Time:48 h under normoxia or hypoxia
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Result:Significantly reduced hypoxia-induced VEGF protein secretion into conditioned media.
Had minimal effect on VEGF levels under normoxia.
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Cell Line:LN229 human glioblastoma cells
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Concentration:10 μM
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Incubation Time:under normoxia or hypoxia
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Result:Significantly reduced hypoxia-induced CAIX protein levels.
Had no effect on Akt protein levels.
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Cell Line:LN229 human glioblastoma cells
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Concentration:25 μM
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Incubation Time:12, 24, 36, 48 h under hypoxia
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Result:Did not significantly alter HIF-1α, HIF-1β, or p300 protein levels in hypoxic LN229 cells across all tested time points.
KCN1 (60 mg/kg, i.p.; 5 days per week for 10 consecutive weeks) potently inhibits the growth of subcutaneous glioblastoma xenografts in athymic nu/nu nude mice, while also suppressing HIF activity and VEGF production in tumors, with extremely low systemic toxicity[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:nu/nu (female, 4-6 weeks old, subcutaneous xenograft model)[2]
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Dosage:30 mg/kg; 60 mg/kg
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Administration:i.p.; 5 days/week; 6 weeks
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Result:Achieved 43% tumor growth inhibition at 30 mg/kg dose.
Achieved 57% tumor growth inhibition at 60 mg/kg dose.
Showed no significant differences in body weight between treated mice and controls.
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Animal Model:Athymic nu/nu nude mice (subcutaneous xenograft via flank injection of 5×106 LN229HRE-luc/lacZ human glioblastoma cells)[3]
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Dosage:60 mg/kg (prevention treatment); 60 mg/kg (pre-established acute treatment); 60 mg/kg (pre-established late treatment)
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Administration:i.p.; 5 days per week; 10 weeks (prevention treatment); i.p.; single dose (pre-established acute treatment); i.p.; 5 days per week (pre-established late treatment)
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Result:Reduced average tumor volume by >4-fold compared to vehicle controls after 10 weeks of treatment.
Induced complete regression in 10 out of 42 tumors after 4-6 weeks, and stable disease in 6 additional tumors.
Lowered average tumor weight by ~3-fold compared to controls.
Significantly reduced tumor growth rates.
Showed significant anti-tumor activity in pre-established tumors (~26 mm3), though less potent than when used as a prevention agent.
Significantly reduced in vivo expression of hypoxia-inducible genes Angptl4, CA9, and VEGF in pre-established tumors after a single dose.
Reduced average tumor HIF-dependent luciferase activity and average tumor VEGF protein levels compared to controls after 10 weeks of treatment.
Was well tolerated with no signs of significant systemic toxicity; reversible liver swelling was observed, likely related to the formulation.
Chemical Information
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No. CAS 927823-01-6
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Peso molecular 465.56
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Fòrmula C26H27NO5S
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SMILES
O=S(C1=CC=C(C(OC)=C1)OC)(N(C2=CC=CC=C2)CC3=CC4=C(C=C3)OC(C)(C)C=C4)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Shi Q, et al. Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor. ACS medicinal chemistry letters. 2012 Aug 09;3(8):620-5. [Content Brief]
[2]. Wang W, et al. KCN1, a novel synthetic sulfonamide anticancer agent: in vitro and in vivo anti-pancreatic cancer activities and preclinical pharmacology. PloS one. 2012;7(9):e44883. [Content Brief]
[3]. Yin S, et al. Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP. Clin Cancer Res. 2012 Dec 15;18(24):6623-33. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
KCN1 Related Classifications
HY-123009 Related Classifications
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- KCN1
- 927823-01-6
- KCN 1
- KCN-1
- HIF/HIF Prolyl-Hydroxylase
- Histone Acetyltransferase
- Apoptosis
- Carbonic Anhydrase
- VEGFR
- GLUT
- p300 CH1 domain
- HPAC human pancreatic cancer cells
- CBP
- LN229 human glioma cells
- BxPC3 human pancreatic cancer cells
- Mia Paca-2 human pancreatic cancer cells
- mouse tumor xenografts
- Panc-1 human pancreatic cancer cells
- HIF-1α
- intracranial glioma models
- Inhibitor
- inhibitor
- inhibit