Development of inhibitor-directed enzyme prodrug therapy (IDEPT) for prostate cancer
Stacy E Martin1, Tanushree Ganguly, Gerhard R Munske
1School of Molecular Biosciences and §Department of Chemistry, Washington State University , Pullman, Washington 99164-7520, United States.
Abstract:
Prostate cancer (PCa) is the second most common cause of cancer death among American men after lung cancer. Unfortunately, current therapies do not provide effective treatments for patients with advanced, metastatic, or hormone refractory disease. Therefore, we seek to generate therapeutic agents for a novel PCa treatment strategy by delivering a suicide enzyme (yCDtriple) to a cell membrane bound biomarker found on PCa cells (prostate-specific membrane antigen (PSMA)). This approach has resulted in a new PCa treatment strategy reported here as inhibitor-directed enzyme prodrug therapy (IDEPT). The therapeutic agents described were generated using a click chemistry reaction between the unnatural amino acid (p-azidophenylalanine (pAzF)) incorporated into yCDtriple and the dibenzylcyclooctyne moiety of our PSMA targeting agent (DBCO-PEG4-AH2-TG97). After characterization of the therapeutic agents, we demonstrate significant PCa cell killing of PSMA-positive cells. Importantly, we demonstrate that this click chemistry approach can be used to efficiently couple a therapeutic protein to a targeting agent and may be applicable to the ablation of other types of cancers and/or malignancies.
Insights
Researchers developed a novel prostate cancer (PCa) therapy using click chemistry to link a suicide enzyme to a PCa biomarker. This inhibitor-directed enzyme prodrug therapy (IDEPT) effectively killed cancer cells.
Area of Science:
- Oncology
- Biochemistry
- Drug Delivery
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men.
- Current treatments are ineffective for advanced, metastatic, or hormone-refractory PCa.
- Targeting cell surface biomarkers offers a potential therapeutic avenue.
Purpose of the Study:
- To develop a novel therapeutic strategy for PCa targeting prostate-specific membrane antigen (PSMA).
- To create therapeutic agents using click chemistry for targeted cancer cell killing.
- To evaluate the efficacy of inhibitor-directed enzyme prodrug therapy (IDEPT) in PCa.
Main Methods:
- Incorporation of an unnatural amino acid (p-azidophenylalanine) into a suicide enzyme (yCDtriple).
- Utilizing click chemistry to conjugate yCDtriple with a PSMA-targeting agent (DBCO-PEG4-AH2-TG97).
- Characterization and in vitro testing of the generated therapeutic agents against PCa cells.
Main Results:
- Successfully synthesized therapeutic agents via click chemistry.
- Demonstrated significant killing of PSMA-positive prostate cancer cells.
- Validated the efficiency of coupling therapeutic proteins to targeting agents.
Conclusions:
- IDEPT represents a novel and effective strategy for PCa treatment.
- Click chemistry is a viable method for creating targeted protein-based therapeutics.
- This approach holds potential for treating other cancers and malignancies.
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