Prochelators as Targeted Prodrugs for Prostate Cancer
Globally, prostate cancer is the second-leading cause of new cancer cases in men and the sixth-leading cause of cancer-related death in men. Prostate-related health issues are on the rise, and the number of cancer cases is increasing, leading to the need for improved treatments and diagnostic technologies. While 80% of patients with prostate cancer respond favorably to androgen ablation therapy through surgical or medical castration, most patients experience a relapse of the disease within 1-2 years. The use of chemotherapies have improved treatment in these metastatic castration resistant prostate cancers (mCRPCs), but off-target activities of these drugs have necessitated the search for novel and selective drugs for mCRPC. Although copper (Cu) has long been recognized as a factor in cancer cell proliferation, approaches to date do not optimally exploit this aspect for clinical effect. A drug that could manipulate the Cu biology of these cells would be a potent therapeutic for mCRPC and enter a growing global prostate cancer therapeutic market. Furthermore, a drug that is activated only in mCRPC tissue would elude off-target activity and side reactions.
The inventors disclose a series targeted dithiocarbamate (DTC) prodrug constructs designed to selectively affect prostate cancer cells by conditionally affecting the copper biology in prostate cancer microenvironment. The inventors have designed and developed two classes of Cu prochelators, enzyme activated and receptor targeted, in which the active component is DTC, which is the active component of the known drug disulfiram. The inventors predict the targeted DTC derivatives will minimize cellular uptake by normal, healthy cells, which in turn will minimize off-target protein inhibition and undesirable metabolite activity that constitute the usual bioactivities of disulfiram. The inventors show that DTC can be successfully masked from binding Cu(II) and activated with specific trigger, opening an avenue for targeted therapy. Both of the enzyme activated prochelators described have been tested in prostate cancer cells and has shown good efficacy. The γ-glutamyl transferase (GGT) activated prochelator, Glu-DTC also shows very good selectivity among the cancerous GGT overexpressing and non-cancerous cell lines. The inventors have also designed two variations of receptor-targeted prochelators of DTC for selective uptake in cancerous tissues.
- Novel rodrugs designed to exploit the unique microenvironment of drug-resistant cancer cells to conditionally form cytotoxic Cu-dithiocarbamate complexes exclusively in prostate cancer cells
- Potentially minimizes side reactions and off-target pathways that impede disulfiram’s anticancer potential
Duke File (IDF) Number
- Franz, Katherine
- Bakthavatsalam, Subha
- George, Daniel
- Sleeper, Mark
- Zhang, Tian
- Safi R, Nelson ER, Chitneni SK, Franz KJ, George DJ, Zalutsky MR, McDonnell DP. (2014) Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74(20):5819-31.
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- Thomas, Dennis