Abstract |
To activate prodrugs for cancer treatment, an anti-TAG-72 antibody (HuCC49DeltaCH2) was used for delivery of an activation enzyme ( beta-galactosidase) to specifically activate a geldanamycin prodrug (17-AG-C2-Gal) against colon cancer. The geldanamycin prodrug 17-AG-C2-Gal was synthesized by coupling a galactose- amine derivative with geldanamycin at the C-17 position. Molecular docking with two different programs (Affinity and Autodock) showed that the prodrug (17-AG-C2-Gal) was unable to bind to Hsp90; however, the product (17-AG-C2), enzymatically cleaved by beta-galactosidase conjugate, bound to Hsp90 in a similar way as geldanamycin and 17-AG. The computational docking results were further confirmed in experimental testing by the tetrazolium [3-(4,5-dimethythiazol-2-yl)]-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and mass spectrometry. HuCC49DeltaCH2 was chemically conjugated to beta-galactosidase. The antibody- enzyme conjugate was able to target tumor antigen TAG-72 with the well-preserved enzymatic activity to activate 17-AG-C2-Gal prodrug. The released active drug 17-AG-C2 was demonstrated to induce up to 70% AKT degradation and enhance anticancer activity by more than 25-fold compared to the prodrug.
|
Authors | Lanyan Fang, Robert F Battisti, Hao Cheng, Philip Reigan, Yan Xin, Jie Shen, David Ross, Kenneth K Chan, Edward W Martin Jr, Peng George Wang, Duxin Sun |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 49
Issue 21
Pg. 6290-7
(Oct 19 2006)
ISSN: 0022-2623 [Print] United States |
PMID | 17034135
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- 17-amino-17-demethoxygeldanamycin -C2-galactose
- Antibodies, Monoclonal
- Antigens, Neoplasm
- Antineoplastic Agents
- Benzoquinones
- Drug Carriers
- Galactosides
- Glycoproteins
- HSP90 Heat-Shock Proteins
- Indicators and Reagents
- Lactams, Macrocyclic
- Prodrugs
- Tetrazolium Salts
- Thiazoles
- tumor-associated antigen 72
- 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- Proto-Oncogene Proteins c-akt
- beta-Galactosidase
- 17-aminogeldanamycin
- geldanamycin
|
Topics |
- Antibodies, Monoclonal
(chemistry)
- Antigens, Neoplasm
(immunology)
- Antineoplastic Agents
(administration & dosage, chemistry, pharmacology)
- Benzoquinones
(chemistry)
- Cell Line, Tumor
- Colonic Neoplasms
- Drug Carriers
- Drug Delivery Systems
- Galactosides
(administration & dosage, chemistry)
- Glycoproteins
(immunology)
- HSP90 Heat-Shock Proteins
(chemistry, metabolism)
- Humans
- Indicators and Reagents
- Lactams, Macrocyclic
(administration & dosage, chemistry)
- Mass Spectrometry
- Models, Molecular
- Prodrugs
(administration & dosage, chemistry, pharmacology)
- Protein Binding
- Proto-Oncogene Proteins c-akt
(metabolism)
- Tetrazolium Salts
- Thiazoles
- beta-Galactosidase
(chemistry)
|