Targeted Prodrugs to Manipulate Copper Biology of Prostate Cancer
Cancer cells have considerably different metallome than normal cells. Especially prostate cancer has been shown to overexpress several important copper trafficking proteins and recruit high levels of copper, making it more sensitive towards drugs like disulfiram.1 Disulfiram acts by altering the copper biology of prostate cancer. Though disulfiram is a promising anticancer agent, the off-target activities lead to adverse side effects.2 Disulfiram’s off-target effects can be mitigated in the cancer setting by chemical modification of the active pharmacophore, dithiocarbamate, in ways that target it preferentially to prostate cancer cells.3 In this seminar, I will present the design, development, and activity of dithiocarbamate prodrug, a Cu prochelator, that is activated in the prostate cancer microenvironment specifically.
(1) Safi, R.; Nelson, E. R.; Chitneni, S. K.; Franz, K. J.; George, D. J.; Zalutsky, M. R.; McDonnell, D. P. Copper signaling axis as a target for prostate cancer therapeutics.Cancer Res 2014, 74, 5819.
(2) Schweizer, M. T.; Lin, J.; Blackford, A.; Bardia, A.; King, S.; Armstrong, A. J.; Rudek, M. A.; Yegnasubramanian, S.; Carducci, M. A. Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer.Prostate Cancer Prostatic Dis 2013, 16, 357.
(3) Bakthavatsalam, S.; Sleeper, M. L.; Dharani, A.; George, D. J.; Zhang, T.; Franz, K. J. Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells.Angew. Chem. Int. Ed. 2018, 57, 12780.