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Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Dec 09; Vol. 64 (23), pp. 17123-17145. Date of Electronic Publication: 2021 Nov 19. - Publication Year :
- 2021
-
Abstract
- Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77-85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (-)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.
- Subjects :
- Cell Line, Tumor
Coordination Complexes chemical synthesis
Humans
Male
Microsomes, Liver enzymology
Microsomes, Liver metabolism
Prostatic Neoplasms pathology
Reactive Oxygen Species metabolism
Xenograft Model Antitumor Assays
Antigens, Surface chemistry
Coordination Complexes chemistry
Coordination Complexes pharmacology
Glutamate Carboxypeptidase II chemistry
Oligopeptides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34797052
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01157