KBJK557
KBJK557 is a Plk1 PBD inhibitor with a human-derived IC50 value of 3.05 μM. KBJK577 binds to Plk1 PBD through electrostatic interactions, π-π stacking, hydrogen bonds, salt bridges and hydrophobic interactions, thereby disrupting the subcellular localization and function of Plk1. KBJK557 induces mitotic arrest, S-phase delay, G2/M-phase arrest and apoptosis, and inhibits cancer cell proliferation. KBJK557 can be used in research related to cancer and non-small cell lung cancer.
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- No. CAS: 2660138-04-3
- Fòrmula: C24H22N6O4
- Peso molecular:458.47
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Actividad biológica
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PLK1 PBD 3.05 μM (IC50) |
KBJK557 (compound 10d) (increasing concentrations; 10 min) potently inhibits Plk1 PBD binding with an IC50 of 16.35 μM[1].
KBJK557 (increasing concentrations; 10 min) selectively inhibits Plk1 PBD with an IC50 of 3.05 μM, showing 2.5-fold selectivity over Plk2 PBD and no binding to Plk3 PBD[1].
KBJK557 (200 μM; 18 h) delocalizes Plk1 from kinetochores in HeLa cells, reducing Plk1 signal intensity by 60.95%[1].
KBJK557 (increasing concentrations; 30 min) inhibits Plk1 PBD through specific interaction, not via non-specific PAINS behavior, as L-cysteine does not reduce its inhibitory activity[1].
KBJK557 inhibits PLK1 PBD with an IC50 of 3 μM and PLK2 PBD with an IC50 of 7.5 μM via non-covalent, pocket-specific interactions in an in vitro FP assay[2].
KBJK557 (50 ns) potently binds to the PLK1 polo-box domain through strong electrostatic interactions with His538, Lys540, and Trp414, plus hydrophobic interactions in the Tyr-rich pocket, with key PIE values ranging from -25 kcal/mol to -21.232 kcal/mol for the highest-affinity residues[3].
KBJK557 (100 ns) maintains moderate direct interactions with the phosphate pocket residues His538 and Lys540, and low direct interactions with the Tyr-rich pocket residues Tyr417 and Tyr485 of the PLK1 polo-box domain[3].
KBJK557 (2 ns) bound to the PLK1 polo-box domain has four unfavorable hydration sites in the Tyr-rich pocket, suggesting potential for enhanced binding affinity by extending ligand moieties into this pocket[3].
KBJK557 (200 μM; 24 h) induces G2/M arrest (27.12% of cells) and delays S-phase progression (18.41% of cells) in HeLa cells[1].
KBJK557 (200 μM; 24-48 h) induces apoptotic cell death in 24.6% of HeLa cells after 24 h and 71.1% after 48 h[1].
KBJK557 (12.5-600 μM; 24 h) potently reduces viability of A549, PC9, and H1975 NSCLC cells with IC50 values of 420 μM, 350 μM, and 400 μM, respectively, following 24 h of treatment[4].
KBJK557 (400 μM; 24 h) induces G2/M phase cell cycle arrest in A549, PC9, and H1975 NSCLC cells[4].
KBJK557 (400 μM; 24 h) induces apoptosis in A549 (57%), PC9 (24%), and H1975 NSCLC cells[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HeLa cells
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Concentration:200 μM
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Incubation Time:18 h
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Result:Reduced Plk1 signal intensity at kinetochores by 60.95% compared to DMSO-treated control cells.
Indicated delocalization of Plk1 from its endogenous kinetochore localization sites.
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Cell Line:HeLa cells
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Concentration:200 μM
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Incubation Time:24 h
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Result:Induced G2/M cell cycle arrest, with 27.12% of cells in the G2/M phase (compared to 18% in control cells).
Significantly delayed S-phase progression, with 18.41% of cells in S-phase (compared to 7.86% in control cells).
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Cell Line:HeLa cells
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Concentration:200 μM
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Incubation Time:24 h, 48 h
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Result:Induced apoptotic cell death in 24.6% of cells after 24 h incubation.
Induced apoptotic cell death in 71.1% of cells after 48 h incubation.
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Cell Line:A549, PC9, H1975 non-small cell lung cancer (NSCLC) cells
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Concentration:12.5 μM, 25 μM, 50 μM, 100 μM, 200 μM, 400 μM, 500 μM, 600 μM
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Incubation Time:24 h
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Result:Decreased cell viability in a dose-dependent manner across all three cell lines.
Reduced A549 cell viability with an IC50 of 420 μM.
Reduced PC9 cell viability with an IC50 of 350 μM.
Reduced H1975 cell viability with an IC50 of 400 μM.
Confirmed a substantial reduction in cancer cell numbers via microscopic imaging.
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Cell Line:A549, PC9, H1975 NSCLC cells
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Concentration:400 μM
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Incubation Time:24 h
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Result:Induced significant G2/M phase arrest in all three cell lines.
Decreased A549 cell G1 phase population by 23%, increased S phase population by 10%, and increased G2/M phase population by 12%.
Decreased PC9 cell G1 phase population by 4%, decreased S phase population by 36%, and increased G2/M phase population substantially.
Decreased H1975 cell G1 phase population by 16%, increased S phase population by 11%, and increased G2/M phase population by 4%.
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Cell Line:A549, PC9, H1975 NSCLC cells
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Concentration:400 μM
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Incubation Time:24 h
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Result:Induced significant apoptosis in all three cell lines.
Induced 57% apoptosis in A549 cells.
Induced 24% apoptosis in PC9 cells.
Induced 35% apoptosis in H1975 cells.
| Species | Dose | Route | AUClast | AUC0-∞ | T1/2 | CL | Vss | MRT |
|---|---|---|---|---|---|---|---|---|
| Mice[1] | 5 mg/kg | i.v. | 11504.31 ng·h/mL | 11535.29 ng·h/mL | 7.73 h | 0.43 L/h/kg | 0.31 L/kg | 0.72 h |
KBJK557 (5 mg/kg; i.v.; single dose) demonstrates favorable pharmacokinetic properties in male ICR mice, including an intermediate half-life of 7.73 h and sufficient systemic exposure following intravenous administration at 5 mg/kg[1].
KBJK557 (5 mg/kg; i.v.; once daily; 29 days) exhibits significant antitumor activity in HeLa xenograft mice, achieving a 60.78% tumor growth reduction on day 25 of treatment without causing notable body weight loss[1].
KBJK557 (15 mg/kg; i.v.; every 3-4 days; 18 days) inhibits A549 non-small cell lung cancer tumor growth by approximately 60% in nude mice without affecting body weight[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c nu/nu nude mice (male, 5 to 8 weeks old, subcutaneous xenograft model induced by HeLa cells)[1]
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Dosage:5 mg/kg
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Administration:i.v.; single dose
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Result:Accumulated in HeLa xenograft tumors, with fluorescence signal intensities in tumors being ~2.1-fold, ~3.9-fold, ~4.11-fold, and ~4.2-fold higher than in muscle at 6, 24, 30, and 48 h post-injection, respectively.
Reached tumor average radiance of 1.78 × 109 p/s/cm2/sr at 24 h and 1.31 × 109 p/s/cm2/sr at 48 h.
Detected high fluorescence signal in liver, kidney, heart, and spleen, with signal intensity in these organs decreasing over time.
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Animal Model:BALB/c nu/nu nude mice (male, 5 weeks old, subcutaneous xenograft model induced by HeLa cells)[1]
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Dosage:5 mg/kg
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Administration:i.v.; once daily; 29 days
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Result:Significantly suppressed tumor growth compared to the PBS control group, achieving a 60.78% reduction in tumor growth relative to the control on day 25 of treatment.
Caused no dramatic changes in body weight, indicating no significant treatment-related toxicity.
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Animal Model:ICR mice (male)[1]
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Dosage:5 mg/kg
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Administration:i.v.; single dose
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Result:Had a plasma elimination half-life (t1/2) of 7.73 h, total clearance (CL) of 0.43 L/h/kg, steady-state volume of distribution (Vss) of 0.31 L/kg, area under the plasma concentration-time curve from time zero to last measurable concentration (AUClast) of 11,504.31 h·ng/mL, and area under the plasma concentration-time curve from time zero to infinity (AUC∞) of 11,535.29 h·ng/mL.
Showed partition coefficients (tissue AUClast/plasma AUClast) of 0.166 for liver, 0.045 for spleen, and 0.182 for kidney.
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Animal Model:BALB/c nu/nu nude mice (male, 6 weeks old, subcutaneous injection of 1 × 106 A549 cells)[4]
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Dosage:15 mg/kg
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Administration:i.v.; every 3-4 days; 18 days
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Result:Reduced tumor volume significantly relative to controls, with an approximate 60% inhibition of tumor growth.
Lowered tumor weight significantly compared to controls.
Left mouse body weights unchanged throughout the treatment period, indicating no treatment-related toxicity.
Chemical Information
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No. CAS 2660138-04-3
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Peso molecular 458.47
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Fòrmula C24H22N6O4
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SMILES
O=C1NC(/C(C(N1)=O)=C/C2=CN(CCNC(C3=CC=C(NC)C=C3)=O)N=C2C4=CC=CC=C4)=O
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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
[1]. Gunasekaran P, et al. Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models. Journal of medicinal chemistry. 2020 Dec 10;63(23):14905-14920. [Content Brief]
[2]. Stafford JM, et al. Inhibitors of the PLK1 polo-box domain: drug design strategies and therapeutic opportunities in cancer. Expert opinion on drug discovery. 2023 Jan;18(1):65-81. [Content Brief]
[3]. Jin H, et al. Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design. International journal of molecular sciences. 2023 Oct 27;24(21):15639. [Content Brief]
Calculators
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