AG-012986 dihydrochloride
For research use only. We do not sell to patients.
- CAS No.: 486414-32-8
- Formula: C22H25Cl2F2N5O2S
- Molecular Weight:532.43
-
Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
-
Biological Activity
-
Chemical Information
- Purity & Documentation
- References
-
Help & FAQs
Biological Activity
Description
IC50 & Target
[1]|
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) |
In Vitro
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.
-
Cell Line:HCT116 human colon cancer cells
-
Concentration:60 nM; 120 nM; 240 nM
-
Incubation Time:8 h; 24 h
-
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.
-
Cell Line:HCT116 human colon cancer cells
-
Concentration:30 nM; 60 nM; 120 nM; 240 nM; 480 nM; 720 nM; 1 μM
-
Incubation Time:24 h; <8 h
-
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.
-
Cell Line:HCT116 human colon cancer cells
-
Concentration:120 nM; 240 nM
-
Incubation Time:8 h; 24 h
-
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.
-
Cell Line:SW620 human colon carcinoma cells
-
Concentration:10 nM; 100 nM; 1000 nM
-
Incubation Time:8 h; 24 h; 72 h; 320 h
-
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.
-
Cell Line:human Müller cell line MIO-M1
-
Concentration:200 nM; 500 nM
-
Incubation Time:24 h
-
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.
-
Cell Line:primary human PBMCs
-
Concentration:50 nM; 200 nM
-
Incubation Time:8 h
-
Result:Induced cleavage of caspase-3 and PARP.
-
Cell Line:purified primary human T cells
-
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)
-
Incubation Time:20 min
-
Result:Showed almost a complete lack of active capase-3 after 24 h stimulation with CD3 antibody.
-
Cell Line:purified primary human T cells
-
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)
-
Incubation Time:20 min
-
Result:Inhibited both basal and α-CD3-induced p38 phosphorylation in purified primary human T cells with or without stimulation.
-
Cell Line:human donor PBMCs
-
Concentration:250 nM
-
Incubation Time:16 h
-
Result:Induced apoptosis in approximately 80% of the cells.
-
Cell Line:human donor PBMCs
-
Concentration:50 nM; 200 nM
-
Incubation Time:8 h
-
Result:Induced the presence of p17 and p19 and the cleaved form of PARP.
Parmacokinetics
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
-
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]
-
Dosage:20 mg/kg; 40 mg/kg; 8.8 mg/kg; 17.5 mg/kg; 35 mg/kg
-
Administration:s.c.; once a day for 12 d
-
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.
-
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]
-
Dosage:10 mg/kg; 20 mg/kg; 40 mg/kg
-
Administration:i.p.; single application
-
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
-
CAS No. 486414-32-8
-
Molecular Weight 532.43
-
Formula C22H25Cl2F2N5O2S
-
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
-
Shipping
Room temperature in continental US; may vary elsewhere.
-
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
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
AG-012986 dihydrochloride Related Classifications
HY-182470 Related Classifications
Powered by Bioz