NSC666715
NSC666715 is a DNA polymerase β (Pol-β) inhibitor. NSC666715 directly and specifically interacts with Pol-β, interferes with its binding to damaged DNA, blocks its dRP lyase activity, and inhibits Pol-β-mediated SN- and LP-BER. NSC666715 induces AP site accumulation and S-phase cell cycle arrest, and triggers senescence and apoptosis (apoptosis) via the p53/p21 pathway in colorectal cancer cells. NSC666715 enhances TMZ (HY-17364)-induced DNA damage, senescence and apoptosis, and potentiates the cytotoxicity of TMZ. NSC666715 inhibits tumor growth in colon cancer xenograft models. NSC666715 can be used in research related to colorectal cancer.
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- CAS No.: 170747-33-8
- Formule: C15H13Cl2N5O2S2
- Masse moléculaire:430.33
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Stockage:
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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DNA Polymerase |
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Cell Line
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Type | Value | Description | References |
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| MCF7 | IC50 |
7.4 μM
Compound: 11c
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Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay
Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay
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[PMID: 38516586] |
| MDA-MB-231 | IC50 |
8.4 μM
Compound: 11c
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Antiproliferative activity against human MDA-MB-231 cells incubated for 72 hrs by MTT assay
Antiproliferative activity against human MDA-MB-231 cells incubated for 72 hrs by MTT assay
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[PMID: 38516586] |
NSC666715 (0-50 μM; 45 min) potently inhibits Fen1-mediated Pol-β strand displacement activity and blocks the LP-BER pathway in an in vitro reconstitution system, with complete inhibition observed at a concentration of 50 μM[1].
NSC666715 (25 μM; 2 h) increases the apurinic/apyrimidinic (AP) site load in HCT116 cells, and when combined with 500 μM TMZ (HY-17364), it further enhances TMZ-induced AP site accumulation[1].
NSC666715 (50 μM; 48 h) increases p21 levels in HCT116 (p53+/+) cells; when combined with TMZ, it enhances the induced expression of p53 and p21[1].
Combination treatment with NSC666715 (50 μM; 2 h) and TMZ maintains S-phase arrest, which can be abrogated by PFTα (HY-15484)[1].
NSC666715 (10-100 μM; 2 h) enhances temozolomide (TMZ)-induced senescence in HCT116 cells, and this effect depends on the p53/p21 pathway[1].
NSC666715 (50 μM; 2 h) enhances the apoptotic signaling pathway induced by TMZ in HCT116 cells: when combined with TMZ, it downregulates the expression of the anti-apoptotic protein Bcl2, upregulates the expression of the pro-apoptotic protein Bax, activates caspase 3 and induces PARP1 cleavage via a caspase-dependent, AIF-independent pathway[1].
NSC666715 (5-15 μM) potently inhibits the strand displacement activity and 1-nt incorporation activity of purified human Pol-β[2].
NSC666715 dose-dependently inhibits the dRP lyase activity of purified human Pol-β, with an IC50 of 4.1 μM[2].
NSC666715 inhibits purified human Pol-β-mediated SN-BER in a dose-dependent manner, with an IC50 of 3.8 μM[2].
NSC666715 dose-dependently inhibits the LP-BER activity mediated by purified human Pol-β[2].
NSC666715 (10 μM) significantly reduces the ability of purified human Pol-β to bind gapped DNA[2].
NSC666715 (25-100 μM; 1 h pretreatment, followed by 48 h TMZ co-treatment) dose-dependently enhances the cytotoxicity of TMZ in mismatch repair-deficient HCT-116-APC (WT), HCT-116-APC (KD) and mismatch repair-proficient HCT-116+ch3 human colon cancer cells[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HCT116 (p53+/+) human colon cancer cells
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Concentration:50 μM (NSC666715); 500 μM (TMZ)
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Incubation Time:48 h
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Result:Did not affect p53 levels but increased p21 levels when used alone.
Combination treatment with TMZ increased both p53 and p21 levels to a similar extent as their individual treatments.
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Cell Line:HCT116 human colon cancer cells
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Concentration:50 μM (NSC666715); 500 μM (TMZ); 10, 20, 30 μM (PFTα)
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Incubation Time:2 h (pretreatment); 48 h (TMZ treatment)
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Result:Had no effect on cell cycle phase distribution when used alone, with 83% of cells in G0/G1, 11% in S phase, 6% in G2/M, and 2% in sub-G1 (apoptosis).
When combined with TMZ, the percentage of cells in S phase was 21% (with 10 μM PFTα), 20% (with 20 μM PFTα), and 21% (with 30 μM PFTα), which was reduced compared to TMZ alone.
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Cell Line:HCT116 human colon cancer cells
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Concentration:50 μM (NSC666715); 500 μM (TMZ); 10, 20, 30 μM (PFTα)
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Incubation Time:2 h (pretreatment); 48 h (TMZ treatment)
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Result:Had no effect on Bcl2 or Bax levels when used alone.
Combined with TMZ, decreased Bcl2 levels and increased Bax levels.
Combination treatment also increased levels of cleaved caspase 3 and cleaved PARP1, while AIF levels remained unchanged.
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Cell Line:MMR-deficient human colon cancer cell lines HCT-116-APC(WT) and HCT-116-APC(KD), MMR-proficient human colon cancer cell line HCT-116+ch3
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Concentration:25 μM, 50 μM, 100 μM
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Incubation Time:1 h pretreatment, followed by 48 h TMZ co-treatment
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Result:Enhanced TMZ cytotoxicity in all three cell lines in a dose-dependent manner.
Reduced TMZ IC50 for HCT-116-APC(WT) from 312 μM to 156 μM (25 μM NSC666715), 107 μM (50 μM NSC666715), and 55 μM (100 μM NSC666715).
Reduced TMZ IC50 for HCT-116-APC(KD) from 491 μM to 205 μM (25 μM NSC666715), 178 μM (50 μM NSC666715), and 154 μM (100 μM NSC666715).
Reduced TMZ IC50 for HCT-116+ch3 from 128 μM to 100 μM (25 μM NSC666715) and 24 μM (50 μM NSC666715).
Showed very low cytotoxicity alone at concentrations up to 100 μM.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCID (female, 6-week-old, subcutaneous xenograft of HCT-116-APC(WT), HCT-116-APC(KD), or HCT-116+ch3 human colon cancer cells)[2]
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Dosage:10 mg/kg
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Administration:i.p.; daily; 5 consecutive days
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Result:Reduced xenograft tumor volume by 37% to 54% across all three cell lines.
Further reduced tumor growth by 62% to 71% when combined with temozolomide relative to vehicle control.
Showed no difference in body weight gain compared to vehicle controls.
Chemical Information
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CAS No. 170747-33-8
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Masse moléculaire 430.33
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Formule C15H13Cl2N5O2S2
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SMILES
O=S(C1=CC(C)=C(Cl)C=C1S)(NC2=NN=C(NC3=CC=C(Cl)C=C3)N2)=O
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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.
Pureté et documentation
Références
[1]. Jaiswal AS, et al. NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage, Senescence and Apoptosis in Colorectal Cancer Cells. PLoS One. 2015;10(5):e0123808. Published 2015 May 1. [Content Brief]
[2]. Jaiswal AS, et al. A novel inhibitor of DNA polymerase beta enhances the ability of temozolomide to impair the growth of colon cancer cells. Mol Cancer Res. 2009;7(12):1973-1983. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
NSC666715 Related Classifications
HY-120105 Related Classifications
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