2. Cell Cycle/DNA Damage Apoptosis
  3. CDK Apoptosis
  4. CIRc-014

CIRc-014 is an orally active Cyclin A/B inhibitor with a Cyclin A IC50 of 0.05 μM, Cyclin A Kd of 2.7 nM, Cyclin B IC50 of less than 0.02 μM and Cyclin B Kd of 1.0 nM. CIRc-014 activates the spindle assembly checkpoint and promotes the formation of a complex between Cyclin B and CDK2 by blocking the RxL interaction of Cyclin A/B. CIRc-014 can induce replication stress, DNA damage, mitotic arrest and apoptosis in tumor cells. CIRc-014 showed tumor growth inhibition and regression in NCI-H69 and NCI-H446 small cell lung cancer xenograft models. CIRc-014 can be used for the research of small-cell lung cancer.

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CIRc-014

CIRc-014 Chemical Structure

CAS No. : 3064485-73-7

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CIRc-014 Related Antibodies

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Description

CIRc-014 is an orally active Cyclin A/B inhibitor with a Cyclin A IC50 of 0.05 μM, Cyclin A Kd of 2.7 nM, Cyclin B IC50 of less than 0.02 μM and Cyclin B Kd of 1.0 nM. CIRc-014 activates the spindle assembly checkpoint and promotes the formation of a complex between Cyclin B and CDK2 by blocking the RxL interaction of Cyclin A/B. CIRc-014 can induce replication stress, DNA damage, mitotic arrest and apoptosis in tumor cells. CIRc-014 showed tumor growth inhibition and regression in NCI-H69 and NCI-H446 small cell lung cancer xenograft models. CIRc-014 can be used for the research of small-cell lung cancer[1][2].

IC50 & Target[1]

Cdk1/cyclin B

1 nM (Kd)

cdk2/cyclin A

0.05 μM (IC50)

cdk2/cyclin A

2.7 nM (Kd)

In Vitro

CIRc-014 (Compound 33) (8-point serial dilutions; 2 h) potently and selectively binds to Cyclin A and Cyclin B, with FP IC50 values of 0.050 μM and < 0.02 μM, respectively, and SPR Kd values of 2.7 nM and 1.0 nM, respectively, while showing >12-fold lower affinity for Cyclin E[1].
CIRc-014 (8-10-point serial dilutions; 3 days (WI-38); 5 days (NCI-H1048, NCI-H446, NCI-H69)) potently inhibits proliferation of SCLC cell lines NCI-H1048, NCI-H446, and NCI-H69 with GI50 values of 0.015 μM, 0.042 μM, and 0.004 μM, respectively, and is over 1270-fold less active against nontransformed WI-38 fibroblasts[1].
CIRc-014 potently and selectively inhibits cyclin A1-CDK2 with an IC50 of 0.13 μM and cyclin B-CDK1 with an IC50 below 0.02 μM, while showing significantly reduced activity against cyclin E1-CDK2 with an IC50 of 11.6 μM[2].
CIRc-014 (0.01-1000 nM; 6 days) potently inhibits proliferation of high-E2F SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69)[2].
CIRc-014 (20-2000 nM; 3 days) dose-dependently induces apoptosis (measured via cleaved PARP) in high-E2F SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69)[2].
CIRc-014 (20-2000 nM; 24 hours) dose-dependently induces G2/M phase arrest in high-E2F SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69)[2].
CIRc-014 (300 nM; 2 hours) disrupts the cyclin B1-MYT1 protein-protein interaction in NCI-H1048 SCLC cells[2].
CIRc-014 (300 nM; 2 hours) promotes formation of neomorphic cyclin B1-CDK2 complexes in NCI-H1048 SCLC cells[2].
CIRc-014 (20-2000 nM; 24 hours) dose-dependently activates the spindle assembly checkpoint in high-E2F SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69)[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

CIRc-014 Related Antibodies

Apoptosis Analysis[2]

Cell Line: human SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69, NCI-H82), NSCLC cell lines (A549, HCC4006, NCI-H1299), non-transformed RPE1 cells
Concentration: 0, 20, 200, 2000 nM
Incubation Time: 3 days
Result: Induced cleaved PARP-positive cells in NCI-H1048 cells, NCI-H446 cells and NCI-H69 cells.
Caused < 10% cleaved PARP-positive cells across all concentrations in resistant cell lines (NCI-H82, A549, HCC4006, NCI-H1299, RPE1).

Cell Cycle Analysis[2]

Cell Line: human SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69, NCI-H82), NSCLC cell lines (A549, HCC4006, NCI-H1299), non-transformed RPE1 cells
Concentration: 0, 20, 200, 2000 nM
Incubation Time: 24 hours
Result: Caused dose-dependent G2/M phase accumulation in NCI-H1048 cells.
Caused G2/M phase accumulation in NCI-H446 cells.
Caused G2/M phase accumulation in NCI-H69 cells.
Induced no significant G2/M accumulation in resistant cell lines across concentrations.

Western Blot Analysis[2]

Cell Line: human SCLC cell lines (NCI-H1048, NCI-H446, NCI-H69), NSCLC cell lines (A549, HCC4006, NCI-H1299)
Concentration: 0, 20, 200, 2000 nM
Incubation Time: 24 hours
Result: Increased p-KNL1 levels dose-dependently in sensitive SCLC lines (NCI-H1048, NCI-H446, NCI-H69).
Caused no increase in p-KNL1 levels in resistant NSCLC lines (A549, HCC4006, NCI-H1299).
Parmacokinetics
Species Dose Route CL Vd T1/2 Bioavailability Tmax Cmax AUCinf F
Mice[1] 2 mg/kg i.v. 68.05 mL/min/kg / 1.37 h / / / 489.86 ng·h/mL /
Mice[1] 30 mg/kg p.o. / / 0.99 h / 1.0 h 1210.00 ng/mL 2002.23 ng·h/mL 27.2 %
Mice[1] 100 mg/kg p.o. / / 3.15 h / 0.5 h 2990.00 ng/mL 8112.69 ng·h/mL 34.9 %
Rat[1] 1 mg/kg i.v. 46 mL/min/kg 3.0 L/kg 1.3 h / / / / /
Dog[1] 1 mg/kg i.v. 22.4 mL/min/kg 2.6 L/kg 4.7 h / / / / /
Pig[1] 1 mg/kg i.v. 28 mL/min/kg 1.8 L/kg 1.5 h / / / / /
Mice[1] 6 mg/mL p.o. / / / / / / / 27.2 %
Rat[1] 3 mg/mL p.o. / / / / / / / 17.4 %
Dog[1] 44.7 mg/mL p.o. / / / 22.6 % / / / /
Pig[1] 22.5 mg/mL p.o. / / / 6.2 % / / / /
In Vivo

CIRc-014 (Compound 33) (25-50 mg/kg; p.o.; BID; 14 days) induces dose-dependent tumor growth inhibition and regression in NCI-H69 SCLC xenografts[1].
CIRc-014 (25-100 mg/kg; p.o.; BID/TID; 14 days) induces dose-dependent tumor growth inhibition and regression in NCI-H446 SCLC xenografts[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Hsd:Athymic Nude-Foxn1nu (female, 6-7 weeks old)[1]
Dosage: 25 mg/kg; 50 mg/kg
Administration: p.o.; BID; 14 days
Result: Achieved 53% mean tumor growth inhibition (TGI).
Induced 40% mean tumor regression.
Resulted in mean body weight loss not exceeding 10% over the study.
Animal Model: Hsd:Athymic Nude-Foxn1nu (female, 7-8 weeks old)[1]
Dosage: 25 mg/kg; 50 mg/kg; 100 mg/kg
Administration: p.o.; BID/TID; 14 days
Result: Achieved 79% mean tumor growth inhibition (TGI) at 25 mg/kg PO TID.
Achieved 85% mean TGI at 50 mg/kg PO BID.
Induced 44% mean tumor regression at 100 mg/kg PO BID.
Induced 80% mean tumor regression at 100 mg/kg PO TID.
Showed a clear dose response in tumor regrowth post-treatment, ordered from highest to lowest: 100 mg/kg PO TID, 100 mg/kg PO BID, 50 mg/kg PO BID, 25 mg/kg PO TID.
Resulted in mean body weight loss not exceeding 10% over the study.
Molecular Weight

962.46

Formula

C45H62ClF6N7O7
CAS No.
SMILES

O=C([C@H]1N(C(C2(C(F)(F)F)CC(F)(F)C2)=O)C[C@H](F)C1)N[C@@H](C3CC3)C(N([C@@H]4C(N[C@@H](CC(C)C)C(N(C)[C@@H](CC5=CC(Cl)=CN=C5OC6CC6)C(N(C)CCCCCCC4)=O)=O)=O)C)=O
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Purity & Documentation
References
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CIRc-014 Related Classifications

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Keywords:

CIRc-0143064485-73-7CIRc014CIRc 014CDKApoptosisCyclin dependent kinaseG1-S-checkpoint-compromised cancer cellssmall-cell lung cancerNCI-H446NCI-H69apoptotic cell deathNCI-H1048cyclin Acyclin Bcell cycle regulationE2F-high cancer cellsInhibitorinhibitorinhibit

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