title: A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.
abstract: Uroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Yip
authors.affiliation: Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakemura-Nakatsugawa
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsin-chu, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Nhu Mai
authors.initials: NM
authors.lastname: Vu
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsin-chu, Taiwan.
authors.forename: Yi-Kun
authors.initials: YK
authors.lastname: Chiang
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsin-chu, Taiwan.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Jennifer Y Y
authors.initials: JY
authors.lastname: Kwan
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Jitkova
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Terence
authors.initials: T
authors.lastname: To
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Payam
authors.initials: P
authors.lastname: Zahedi
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada ; Department of Biochemistry, University of Toronto, Ontario, Canada ; Department of Molecular Genetics; University of Toronto, Ontario, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York, United States of America.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Lovell
authors.affiliation: Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Sessler
authors.affiliation: Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada ; Department of Radiation Oncology, Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada ; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C000594639:PI-16 compound; D011166:Porphyrins; D011994:Recombinant Proteins; D014575:Uroporphyrinogen Decarboxylase