AG-012986 dihydrochloride
For research use only. We do not sell to patients.
- CAS No.: 486414-32-8
- Formula: C22H25Cl2F2N5O2S
- Molecular Weight:532.43
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
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CDK1 44 nM (Ki) |
CDK2 94 nM (Ki) |
CDK3/Cyclin E 46 nM (Ki) |
Cdk4/cyclin D3 9.2 nM (Ki) |
CDK5/p35 22 nM (IC50) |
CDK7/cyclin H 0 nM (Ki) |
CDK9/CycT1 4 nM (IC50) |
AG-012986 (dihydrochloride) is a potent, selective pan-CDK inhibitor with nanomolar activity against CDK4/cyclin D3 (Ki = 9.2 nmol/L), CDK1/cyclin B (Ki = 44 nmol/L), CDK2/cyclin A (Ki = 94 nmol/L), CDK9/cyclin T (IC50 = 4 nmol/L), and CDK5/p35 (IC50 = 22 nmol/L)[1].
AG-012986 (dihydrochloride) (0.837-2.44 μmol/L) has limited off-target activity against non-kinase targets, with functional interactions at micromolar concentrations with the calcium type L ion channel, serotonin transporter, and histamine H3 receptor[1].
AG-012986 (dihydrochloride) (72 h) potently inhibits proliferation of 18 human tumor cell lines with an average IC50 of 120 nmol/L, and displays IC50 values <100 nmol/L in 13 of these cell lines, independent of p53 and Rb status[1].
AG-012986 (dihydrochloride) (60-240 nM; 8-24 h) induces dose-dependent hypophosphorylation of Rb Ser795 in HCT116 human colon cancer cells after 24 hours of treatment, with maximal effects at >120 nM, but shows minimal effect after 8 hours[1].
AG-012986 (dihydrochloride) (30 nM-1 μM; 8-24 h) induces G1 phase arrest in HCT116 human colon cancer cells at 30 to 120 nM and G2-M phase arrest at ≥240 nM after 24 hours of treatment, but does not induce cell cycle arrest with <8 hours of exposure[1].
AG-012986 (dihydrochloride) (30-240 nM; 8-24 h) induces apoptosis in HCT116 human colon cancer cells with an IC50 of ≈160 nM after 24 hours of treatment, but shows no apoptotic effect after 8 hours[1].
AG-012986 (dihydrochloride) (10-1000 nM; 8-320 h) shows time-dependent cytotoxicity in SW620 human colon carcinoma cells, with minimal activity after 8 hours, moderate activity (IC50 = 300 nmol/L) after 24 hours, and substantial cytotoxicity (IC50 <100 nmol/L) after ≥72 hours[1].
AG-012986 (dihydrochloride) exhibits binding inhibition of multiple CDK isoforms in a cell-free KINOMEscan assay, with similar IC50 values to non-neurotoxic NVP-2 for CDK11, CDK16, and CDK17[2].
AG-012986 (dihydrochloride) (200-500 nM; 24 h) induces dose-dependent cytotoxicity in human MIO-M1 Müller cells, with significant decreases in cell viability and increases in cell death observed at 200 nM and maximal effects at 500 nM after 24 h of incubation[2].
AG-012986 (dihydrochloride) (250 nM; 16 h) induces rapid apoptosis/necrosis in primary human PBMCs, with 80% of cells showing dual PI/Annexin-V positivity[3].
AG-012986 (dihydrochloride) (50 nM-1 μM; 8-48 h) activates caspase-3/7 in primary human PBMCs in vitro in a dose-dependent manner, with peak activity occurring 16-24 h after treatment with 50 nM, 200 nM, or 1 μM[3].
AG-012986 (dihydrochloride) (50 nM-200 nM; 8 h) induces cleavage of caspase-3 and PARP in primary human PBMCs following 8 h treatment with 50 nM or 200 nM, confirming caspase-mediated apoptosis[3].
AG-012986 (dihydrochloride) (10 nM-500 nM; 16 h) exhibits greater cytotoxicity in primary human PBMCs than staurosporine after 16 h treatment with 10-500 nM, as measured by reduced ATP content and increased caspase-3/7 activity[3].
AG-012986 (dihydrochloride)'s (50 nM-250 nM; 20 min) toxicity profile is altered by acute stimulation of T cells[3].
AG-012986 (dihydrochloride) (20 nM-500 nM) inhibits α-CD3-induced proliferation in purified primary human T cells pretreated by AG-012986 followed by 24 h α-CD3 antibody stimulation, while α-CD3 stimulation decouples this antiproliferative activity from AG-012986-induced toxicity[3].
AG-012986 (dihydrochloride) (20 nM-500 nM; 48 h) inhibits α-CD3-induced IL-2 production in purified primary human T cells in a dose-dependent manner, with a fivefold reduction observed at 20 nM[3].
AG-012986 (dihydrochloride) (50 nM-250 nM; 20 min pretreatment) inhibits both basal and α-CD3-induced p38 phosphorylation in purified primary human T cells pretreated with 50 nM or 250 nM for 20 min followed by 16 h incubation with or without stimulation[3].
AG-012986 (dihydrochloride) (250 nM; 16 h) causes rapidly apoptosis in PBMCs and occurs independently of any cell division[4].
AG-012986 (dihydrochloride) (50-200 nM; 8 h) induced the presence of p17 and p19 and the cleaved form of PARP[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HCT116 human colon cancer cells
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Concentration:60 nM; 120 nM; 240 nM
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Incubation Time:8 h; 24 h
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Result:Showed minimal effect on Rb Ser795 phosphorylation after treatment with up to 240 nM for 8 hours.
Induced dose-dependent hypophosphorylation of Rb Ser795 after treatment with 60 to 240 nM for 24 hours, with maximal effects at >120 nM.
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Cell Line:HCT116 human colon cancer cells
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Concentration:30 nM; 60 nM; 120 nM; 240 nM; 480 nM; 720 nM; 1 μM
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Incubation Time:24 h; <8 h
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Result:Caused accumulation of cells in the G1 phase after treatment with 30 to 120 nM for 24 hours.
Caused accumulation of cells in the G2-M phase after treatment with ≥240 nM for 24 hours.
Failed to induce any cell cycle arrest after transient exposure (<8 hours) to up to 1 μM.
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Cell Line:HCT116 human colon cancer cells
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Concentration:120 nM; 240 nM
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Incubation Time:8 h; 24 h
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Result:Induced no apoptosis after 8 hours of treatment at any concentration.
Induced a greater proportion of apoptotic cells after treatment with ≥120 nM for 24 hours, with an IC50 of ≈160 nM.
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Cell Line:SW620 human colon carcinoma cells
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Concentration:10 nM; 100 nM; 1000 nM
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Incubation Time:8 h; 24 h; 72 h; 320 h
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Result:Showed minimal cytotoxic activity after 8 hours of treatment.
Showed moderate activity with an IC50 of 300 nmol/L after 24 hours.
Showed substantial cytotoxicity with an IC50 <100 nmol/L at treatment durations ≥72 hours, with near-complete cell kill at 1000 nM after 320 hours.
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Cell Line:human Müller cell line MIO-M1
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Concentration:200 nM; 500 nM
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Incubation Time:24 h
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Result:Caused a dose-dependent decrease in cell viability (measured via MTS assay) and a corresponding dose-dependent increase in cell death (measured via LDH release).
Reduced cell viability by ~25% relative to controls at maximal response.
Increased LDH release by ~2-fold relative to controls at maximal response.
Produced significant effects at 200 nM.
Achieved maximal response at 500 nM.
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Cell Line:primary human PBMCs
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Concentration:50 nM; 200 nM
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Incubation Time:8 h
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Result:Induced cleavage of caspase-3 and PARP.
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Cell Line:purified primary human T cells
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Concentration:50 nM; 250 nM; 50 nM plus α-CD3 antibody (1 μg/mL; 24 h); 250 nM plus α-CD3 antibody (1 μg/mL; 24 h)
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Incubation Time:20 min
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Result:Showed almost a complete lack of active capase-3 after 24 h stimulation with CD3 antibody.
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Cell Line:purified primary human T cells
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Concentration:50 nM; 250 nM; 50 nM plus plate-bound α-CD3 antibody (1 μg/mL; 16 h); 250 nM plus plate-bound α-CD3 antibody (1 μg/mL; 16 h)
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Incubation Time:20 min
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Result:Inhibited both basal and α-CD3-induced p38 phosphorylation in purified primary human T cells with or without stimulation.
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Cell Line:human donor PBMCs
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Concentration:250 nM
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Incubation Time:16 h
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Result:Induced apoptosis in approximately 80% of the cells.
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Cell Line:human donor PBMCs
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Concentration:50 nM; 200 nM
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Incubation Time:8 h
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Result:Induced the presence of p17 and p19 and the cleaved form of PARP.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Severe combined immunodeficient; athymic NCr-nu/nu (human tumor xenograft model, implanted s.c. with 2 million COLO205 or H522 cells in 30% Matrigel)[1]
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Dosage:20 mg/kg; 40 mg/kg; 8.8 mg/kg; 17.5 mg/kg; 35 mg/kg
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Administration:s.c.; once a day for 12 d
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Result:Induced 94.7% TGI and a net log tumor cell kill of 1.20 in COLO205 colon carcinoma models at 40 mg/kg daily for 12 days.
Induced 71.3% TGI and a net log tumor cell kill of 0.64 in COLO205 colon carcinoma models at 20 mg/kg daily for 12 days.
Induced 22.2% TGI and a negative net log tumor cell kill of -0.21 in COLO205 colon carcinoma models at 10 mg/kg daily for 12 days.
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Animal Model:Severe combined immunodeficient; athymic NCr-nu/nu (human tumor xenograft model, implanted i.p. with 2 million COLO205 cells in 30% Matrigel)[1]
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Dosage:10 mg/kg; 20 mg/kg; 40 mg/kg
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Administration:i.p.; single application
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Result:Reduced Rb Ser795 phosphorylation by >80% and induced PARP cleavage in COLO205 tumor tissue at 24 hours post single 20 or 40 mg/kg i.p. dose.
Reduced Rb Ser795 phosphorylation by 50% and did not induce PARP cleavage in COLO205 tumor tissue at 24 hours post single 10 mg/kg i.p. dose.
Significantly decreased BrdUrd uptake (S phase activity) in COLO205 tumors between 12 and 24 hours post single 20 mg/kg i.p. dose.
Chemical Information
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CAS No. 486414-32-8
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Molecular Weight 532.43
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Formula C22H25Cl2F2N5O2S
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SMILES
O=C(C1=C(C=CC=C1F)F)C2=C(N)N=C(NC3=CC=C(C=C3)C(N[C@H](C)CN(C)C)=O)S2.Cl.Cl
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
[1]. Zhang C, et al. Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy. Mol Cancer Ther. 2008 Apr;7(4):818-28. [Content Brief]
[2]. Wright P, et al. Differential expression of cyclin-dependent kinases in the adult human retina in relation to CDK inhibitor retinotoxicity. Arch Toxicol. 2019;93(3):659-671. [Content Brief]
[3]. Lee DU, et al. Off-target immune cell toxicity caused by AG-012986, a pan-CDK inhibitor, is associated with inhibition of p38 MAPK phosphorylation. J Biochem Mol Toxicol. 2012 Mar;26(3):101-8. [Content Brief]
Calculators
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