R116010
R116010 is an orally active Retinoic acid (HY-14649) metabolism blocker with an IC50 of 8.7 nM in T47D cells. R116010 inhibits CYP26A1 and CYP26B1, blocking Retinoic acid catabolism. R116010 inhibits CYP17 and human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP2D6. R116010 enhances Retinoic acid-induced gene expression and MYCN downregulation, enhances Retinoic acid-mediated antiproliferative activity, and inhibits tumor growth in a mouse breast cancer model. R116010 can be used for research on neuroblastoma.
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- No. CAS: 201410-54-0
- Fòrmula: C21H23N5S
- Peso molecular:377.51
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Actividad biológica
Descripciòn
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CYP26 10 nM (IC50) |
CYP3A4 0.35 μM (IC50) |
CYP1A2 8.3 μM (IC50) |
CYP2C9 11.0 μM (IC50) |
CYP2C19 5.9 μM (IC50) |
CYP2D6 3.9 μM (IC50) |
CYP17 0.25 μM (IC50) |
MYCN |
In Vitro
R116010 completely inhibits RA metabolism in RA-pretreated T47D human breast cancer cells[1].
R116010 selectively inhibits CYP26A1-mediated RA 4-hydroxylase in T47D microsomes with an IC50 of 4 nM, while its IC50 values for CYP19, CYP2C11, CYP2A1, CYP3A, and CYP2B1/2 are all >10 μM, and its IC50 for CYP17 is 0.25 μM[1].
R116010 (in combination with RA, 0.01 nM-10 μM; 7 days) alone does not affect T47D cell proliferation, but enhances RA-mediated antiproliferative activity in T47D cells, producing a three-fold enhancement at 1 μM, with an IC50 of 0.62 nM[1].
R116010 (1 μM; 24 h) enhances Retinoic acid-induced CYP26B1, CRABPII, and RARβ expression in SH-SY5Y cells and enhances MYCN downregulation in NGP cells, while having no effect on CYP26B1 when used alone[5].
R116010 (1-10 μM; 24 h) selectively increases intracellular ATRA (Retinoic acid) (HY-14649) in SH-SY5Y and NGP cells with high CYP26, but does not increase 13cisRA, and has no effect on SH-EP or GIMEN cells with low CYP26[5].
R116010 (1-10 μM; 24 h) reduces AT-4-oxo-RA formation by 3- to 3.8-fold in SH-SY5Y and NGP cells with high CYP26, while having no effect on SH-EP or GIMEN cells with low CYP26[5].
R116010 (1-1000 nM; 1 h) inhibits CYP26 in MCF-7-derived microsomes with an IC50 of 10 nM[6].
R116010 (1-1000 nM; 1 h) inhibits CYP26A1 in microsomes derived from MCF-7 cells, with an IC50 of 10 nM (0.01 µM)[7].
R116010 (0.4 µM) inhibits CYP3A4 in human liver microsomes with an IC50 of 0.35 µM, and shows weak inhibition of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 (IC50 = 8.3, 11.0, 5.9, and 3.9 µM, respectively)[7].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:T47D human breast cancer cells
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Concentration:0.01 nM; 0.1 nM; 1 nM; 10 nM; 100 nM; 1 μM; 10 μM
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Incubation Time:7 days (medium and compound renewal on days 2 and 5)
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Result:Had no effect on T47D cell proliferation alone.
In combination with RA, enhanced RA-mediated antiproliferative activity in a concentration-dependent manner: 0.01 μM produced a 1.25-fold enhancement (IC50 1.6 nM); 0.1 μM produced a 2.6-fold enhancement (IC50 0.77 nM); 1 μM produced a three-fold enhancement (IC50 0.62 nM).
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Cell Line:SH-SY5Y neuroblastoma cells and NGP neuroblastoma cells
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Concentration:1 μM (alone); 1 μM (with ATRA 0.01 or 0.1 μM); 1 μM (with 13cisRA 0.01 or 0.1 μM)
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Incubation Time:24 h
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Result:Had no effect on CYP26B1 expression in SH-SY5Y cells.
Co-incubation with ATRA or 13cisRA increased CYP26B1 expression compared with either Retinoid alone.
Increased CRABPII and RARβ expression when combined with ATRA 0.01 μM or 13cisRA 0.1 μM compared with Retinoid alone in SH-SY5Y cells.
Produced a small increase in MYCN expression alone in NGP cells.
Enhanced the downregulation of MYCN by ATRA 0.1 μM or 13cisRA 0.1 μM in NGP cells.
The greatest magnitude of response was observed for CYP26B1.
In Vivo
R116010 (1.25-2.5 mg/kg; p.o.; one to four doses; 6 h) co-administration increases plasma and intratumoral 13cisRA and reduces hepatic 4-oxo-RA metabolites in SH-SY5Y xenografts[5].
R116010 (1.25-2.5 mg/kg; p.o.; single or four doses; 6 h) lowers hepatic 4-oxo-RA metabolites and increases plasma ATRA in SH-SY5Y xenografts with ATRA[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:A/J (TA3-Ha cells passaged in A/J and C3D2F1 mice; every fifth passage in A/J mice)[1]
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Dosage:0.08, 0.16, 0.31, 0.63, and 1.25 mg/kg per administration
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Administration:p.o. (oral gavage); twice daily; day 1 through day 21
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Result:Inhibited TA3-Ha tumour growth at doses as low as 0.16 mg/kg.
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Animal Model:CD-1 nude (CD-1 nu/nu; female)[5]
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Dosage:1.25 mg/kg (immediately before 13cisRA); 2.5 mg/kg (immediately before 13cisRA); 2.5 mg/kg (one dose before 13cisRA); 2.5 mg/kg (two doses before 13cisRA); 2.5 mg/kg (four doses before 13cisRA)
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Administration:p.o.; immediately before 13cisRA; one, two, or four doses; 6 h
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Result:In plasma, 13cisRA and ATRA concentrations increased; plasma 13cisRA increased up to 4.6-fold compared with 13cisRA alone after four doses of 2.5 mg/kg.
Plasma 13cis-4-oxo-RA and AT-4-oxo-RA also varied, with no dose-dependent effect for 13cis-4-oxo-RA and an apparent linear increase for AT-4-oxo-RA.
Intratumoral 13cisRA increased from 0.22 to 0.59 μg/g with single-dose 2.5 mg/kg before 13cisRA.
CYP26A1 expression in tumours increased 4- to 20-fold in individual animals after two doses of 2.5 mg/kg with 13cisRA compared with 13cisRA alone.
Tumour ATRA levels were unchanged.
Hepatic 13cis-4-oxo-RA and AT-4-oxo-RA concentrations decreased dose-dependently before 13cisRA, while hepatic 13cisRA was unchanged.
Hepatic ATRA increased with one and two doses of 2.5 mg/kg.
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Animal Model:CD-1 nude (CD-1 nu/nu; female)[5]
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Dosage:1.25 mg/kg (immediately before ATRA); 2.5 mg/kg (immediately before ATRA); 2.5 mg/kg (four doses before ATRA)
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Administration:p.o.; immediately before ATRA; single or four doses; 6 h
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Result:In plasma, four doses of 2.5 mg/kg increased plasma ATRA up to 2.3-fold compared with ATRA alone; plasma 13cisRA showed a small change.
Plasma 13cis-4-oxo-RA was not detectable, and plasma AT-4-oxo-RA was unchanged.
Hepatic 13cis-4-oxo-RA and AT-4-oxo-RA concentrations decreased with ATRA or before ATRA; hepatic 13cisRA and ATRA levels did not increase.
Tumour retinoid levels, tumour 4-oxo-RA metabolites, and tumour CYP26A1 expression did not differ before ATRA.
Chemical Information
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No. CAS 201410-54-0
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Peso molecular 377.51
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Fòrmula C21H23N5S
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SMILES
CN(C)[C@H](C)[C@H](N1C=CN=C1)C2=CC=C(C=C2)NC3=NC4=CC=CC=C4S3
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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
[4]. Ali I, et al. Imidazoles as potential anticancer agents. Medchemcomm. 2017 Apr 13;8(9):1742-1773.
[6]. Gomaa MS, et al. Small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26): synthesis and biological evaluation of imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates. Journal of medicinal chemistry. 2011 Apr 28;54(8):2778-91. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
R116010 Related Classifications
HY-121500A Related Classifications
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