Peptide-drug Conjugate Information
General Information of This Peptide-drug Conjugate (PDC)
| PDC ID |
PDC_00253
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| PDC Name |
OGF-Gem
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| PDC Status |
Investigative
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| Indication |
In total 1 Indication(s)
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| Structure |
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| Peptide Name |
OGF
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Peptide Info | ||||
| Receptor Name |
Opioid growth factor receptor (OGFR)
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Receptor Info | ||||
| Drug Name |
Gemcitabine
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Drug Info | ||||
| Therapeutic Target |
Ribonucleoside-diphosphate reductase subunit M2 (RRM2)
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Target Info | ||||
| Linker Name |
Succinic Acid
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Linker Info | ||||
| Formula |
C40H48F2N8O13S
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| #Ro5 Violations (Lipinski): 4 | Molecular Weight | 918.93 | ||||
| Lipid-water partition coefficient (xlogp) | -1.242 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 9 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 16 | |||||
| Rotatable Bond Count (rotbonds) | 23 | |||||
Full List of Activity Data of This Peptide-drug Conjugate
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Pancreatic ductal adenocarcinoma | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
17.63 ± 2.334 nM
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| Administration Time | 72 h | ||||
| Evaluation Method | MTT assay | ||||
| MOA of PDC |
Therefore, we designed, synthesized, and characterized an OGF-Gem conjugate, where OGF and Gem are tethered by an organic linker (Figure 1). Gem was subjected to selective protection using the tert-butoxycarbonyl (Boc) group and prepared as gemcitabine hemisuccinate. 5-O-diBoc-gemcitabine hemisuccinate was conjugated with the OGF peptide in solution. We demonstrated the cytotoxic activity of the OGF-Gem conjugate against pancreatic cancer cell lines, including the metastatic line (MIA PaCa-2 and AsPC-1). Furthermore, we confirmed that OGF-Gem is either not cytotoxic or significantly less cytotoxic to two non-tumor-transformed human cellskidney (HEK-293) and skin fibroblast cells (HDFa). We also determined the effect of OGF-Gem on cell cycle inhibition, and the inhibition of cell proliferation, senescent cells, and apoptosis. We have demonstrated that OGF-Gem has antimetastatic potential due to inhibited pancreatic tumor cell (AsPC-1)-induced platelet aggregation. This can significantly impact the inhibition of disease progression (metastasis) of pancreatic cancer.
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| Description |
The tested compounds cytotoxic activity was determined using the MTT test, which is based on the ability to convert tetrazole salts to water insoluble formazan through mitochondrial dehydrogenases. Our results show a high cytotoxic effect on all pancreatic cancer cell lines. Exposing pancreatic cell lines MIA PaCa-2 and AsPC-1 to OGF-Gem decreased viability. Importantly, the OGF-Gem conjugate demonstrated a more pronounced cytotoxic effect against the metastatic pancreatic cancer cell line AsPC-1 compared to the commonly used chemotherapeutic agent. The results obtained for non-tumor-transformed cellsa human embryonic kidney line HEK-293 and human primary dermal fibroblast line HDFa presented a slight cytotoxicity effect from the OGF-Gem derivative within 3 days of incubation for all tested concentrations. Interestingly, an 80% reduction in HEK-293 cell viability was observed for the 100 nM Gem compared to the 100 nM OGF-Gem derivative. In HDFa cells, 100 nM Gem reduced viability to 35%, while the OGF-Gem conjugate slightly decreased the viability (to 75% viability) after 72 h of incubation. Based on the analysis of the results, concentrations of 3.125, 12.5, 50, and 100 nM, as well as an incubation time of 72 h, were selected for further experiments on the three pancreatic cancer cell lines.
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| In Vitro Model | Pancreatic ductal adenocarcinoma | MIA PaCa-2 cell | CVCL_0428 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Pancreatic ductal adenocarcinoma | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
27.44 ± 9.161 nM
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| Administration Time | 72 h | ||||
| Evaluation Method | MTT assay | ||||
| MOA of PDC |
Therefore, we designed, synthesized, and characterized an OGF-Gem conjugate, where OGF and Gem are tethered by an organic linker (Figure 1). Gem was subjected to selective protection using the tert-butoxycarbonyl (Boc) group and prepared as gemcitabine hemisuccinate. 5-O-diBoc-gemcitabine hemisuccinate was conjugated with the OGF peptide in solution. We demonstrated the cytotoxic activity of the OGF-Gem conjugate against pancreatic cancer cell lines, including the metastatic line (MIA PaCa-2 and AsPC-1). Furthermore, we confirmed that OGF-Gem is either not cytotoxic or significantly less cytotoxic to two non-tumor-transformed human cellskidney (HEK-293) and skin fibroblast cells (HDFa). We also determined the effect of OGF-Gem on cell cycle inhibition, and the inhibition of cell proliferation, senescent cells, and apoptosis. We have demonstrated that OGF-Gem has antimetastatic potential due to inhibited pancreatic tumor cell (AsPC-1)-induced platelet aggregation. This can significantly impact the inhibition of disease progression (metastasis) of pancreatic cancer.
Click to Show/Hide
|
||||
| Description |
The tested compounds cytotoxic activity was determined using the MTT test, which is based on the ability to convert tetrazole salts to water insoluble formazan through mitochondrial dehydrogenases. Our results show a high cytotoxic effect on all pancreatic cancer cell lines. Exposing pancreatic cell lines MIA PaCa-2 and AsPC-1 to OGF-Gem decreased viability. Importantly, the OGF-Gem conjugate demonstrated a more pronounced cytotoxic effect against the metastatic pancreatic cancer cell line AsPC-1 compared to the commonly used chemotherapeutic agent. The results obtained for non-tumor-transformed cellsa human embryonic kidney line HEK-293 and human primary dermal fibroblast line HDFa presented a slight cytotoxicity effect from the OGF-Gem derivative within 3 days of incubation for all tested concentrations. Interestingly, an 80% reduction in HEK-293 cell viability was observed for the 100 nM Gem compared to the 100 nM OGF-Gem derivative. In HDFa cells, 100 nM Gem reduced viability to 35%, while the OGF-Gem conjugate slightly decreased the viability (to 75% viability) after 72 h of incubation. Based on the analysis of the results, concentrations of 3.125, 12.5, 50, and 100 nM, as well as an incubation time of 72 h, were selected for further experiments on the three pancreatic cancer cell lines.
Click to Show/Hide
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| In Vitro Model | Pancreatic ductal adenocarcinoma | AsPC-1 cell | CVCL_0152 | ||
References
