Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Evaluation of Compound BC-05
2.2.1. BC-05 Is a CD13 and 20S Proteasome Dual Inhibitor
2.2.2. Docking Study of BC-05 with CD13 and 20S Proteasome
2.2.3. BC-05 Displayed Potent Anti-Proliferative Activity toward Cancer Cell Lines
2.2.4. BC-05 Induced Cancer Cell Apoptosis and Cell Cycle Arrest
2.2.5. In Vivo Pharmacokinetic Study of BC-05
2.2.6. BC-05 Exhibits Remarkably Anti-Metastasis Efficacy In Vivo
2.2.7. BC-05 Exhibits Immunostimulating Potency In Vivo
2.2.8. BC-05 Exhibits Superior Anti-Tumor Activity In Vivo
2.2.9. Acute Toxicity Assessment of BC-05 in Healthy Mice
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. CD13 Inhibition Assay [20]
4.3. 20S Proteasome Inhibition Assay
4.4. Molecular Docking
4.5. Cell Proliferation Analysis
4.6. Cell Cycle and Apoptosis Study
4.7. Western Blot Analysis
4.8. In Vivo Pharmacokinetics
4.9. In Vivo H22 Pulmonary Metastasis Model
4.10. In Vivo P3x63Ag8.653 Tumor Transplant Models
4.11. Survival Time in Mice Bearing B16F10 Cells
4.12. Macrophage Phagocytosis by Carbon Clearance Test
4.13. Acute Toxicity Experiment
4.14. Subacute Toxicity Experiment
4.15. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Cpd. | IC50(μM) a toward CD13 from Porcine Kidney | IC50(μM) a toward Human CD13 | IC50(μM) b toward Chymotrypsin-like (CT-L) |
---|---|---|---|
BC-05 | 0.65 ± 0.05 | 0.13 ± 0.01 | 1.39 |
Ixazomib | >20 | N.D. | 0.0024 |
Ubenimex | 4.91 ± 0.13 | 2.03 ± 0.18 | >10 |
Cell Lines | BC-05 | Ixazomib | Ubenimex |
---|---|---|---|
U266 | 13.66 ± 1.43 | 0.12 ± 0.01 | >200 |
RPMI-8266 | 15.12 ± 2.23 | 0.098 ± 0.01 | >200 |
ARP-1 | 10.23 ± 1.23 | 0.099 ± 0.002 | >200 |
MM.1S | 1.53 ± 0.24 | 0.007 ± 0.002 | >200 |
HEL | 13.26 ± 2.81 | 0.11 ± 0.003 | >200 |
KG1 | 41.55 ± 4.11 | 0.40 ± 0.05 | >200 |
P3x63Ag8.653 | 17.73 ± 0.75 | 0.08 ± 0.005 | >200 |
SP2 | 14.67 ± 4.91 | 0.074 ± 0.017 | >200 |
A2780 | 33.71 ± 0.99 | 0.11 ± 0.01 | >200 |
HCT116 | 86.66 ± 7.34 | 0.02 ± 0.01 | >200 |
Hela | 83.11 ± 8.79 | 0.74 ± 0.19 | >200 |
MDA-MB-231 | 13.30 ± 0.49 | 0.12 ± 0.01 | >200 |
HT-29 | 12.51 ± 1.21 | 0.06 ± 0.001 | >200 |
U251 | 47.54 ± 11.89 | 0.92 ± 0.86 | >200 |
PC3 | 47.41 ± 4.22 | 0.75 ± 0.12 | >200 |
HEK293 | >200 | 17.10 ± 2.27 | >200 |
HL-7702 | >200 | 4.04 ± 0.63 | >200 |
BC-05 | BC-05 | |
---|---|---|
Administered dose (mg/kg) | i.v. at 10 mg/kg | oral at 10 mg/kg |
AUC0–∞ (μg/L∗h) | 5154.34 ± 482.30 | 1307.71 ± 116.74 |
t1/2 (h) | 1.72 ± 0.67 | 2.35 ± 1.23 |
CL (L/h/kg) | 1.95 ± 0.18 | 7.69 ± 0.66 |
Tmax (h) | 0.03 ± 0 | 2.0 ± 0 |
Cmax (ng/mL) | 10,488.6 ± 1414.99 | 373.2 ± 49.65 |
F (%) | -- | 24.9 ± 4.32 |
Groups | Dosage (mmol/kg) | Carbon Clearance Index (K) a | Phagocytosis Index (α) a |
---|---|---|---|
Ctrl | 0 | 0.057 ± 0.0061 | 5.36 ± 0.19 |
Ixazomib | 0.008 | 0.045 ± 0.0092 | 5.00 ± 0.34 |
BC-05 | 0.006 | 0.066 ± 0.0077 | 6.60 ± 0.26 |
BC-05 | 0.008 | 0.076 ± 0.0016 | 6.61 ± 0.05 |
Groups | Survival Animals |
---|---|
Vehicle | 10/10 |
BC-05 (0.27 mmol/kg) | 10/10 |
BC-05 (0.36 mmol/kg) | 6/10 |
BC-05 (0.49 mmol/kg) | 4/10 |
BC-05 (0.65 mmol/kg) | 1/10 |
BC-05 (0.86 mmol/kg) | 0/10 |
Ixazomib (0.04 mmol/kg) | 0/10 |
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Zhang, J.; Sun, S.; Liu, J.; Zhang, L.; Guo, D.; Zhang, N.; Zhao, J.; Kong, D.; Xu, T.; Wang, X.; et al. Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer. Molecules 2023, 28, 6343. https://doi.org/10.3390/molecules28176343
Zhang J, Sun S, Liu J, Zhang L, Guo D, Zhang N, Zhao J, Kong D, Xu T, Wang X, et al. Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer. Molecules. 2023; 28(17):6343. https://doi.org/10.3390/molecules28176343
Chicago/Turabian StyleZhang, Jian, Simin Sun, Jinyu Liu, Liang Zhang, Di Guo, Naixin Zhang, Jun Zhao, Dexin Kong, Tongqiang Xu, Xuejian Wang, and et al. 2023. "Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer" Molecules 28, no. 17: 6343. https://doi.org/10.3390/molecules28176343