title: Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules.
abstract: Deoxycytidine kinase (dCK) is a key enzyme in the nucleoside salvage pathway that is also required for the activation of several anticancer and antiviral nucleoside analog prodrugs. Additionally, dCK has been implicated in immune disorders and has been found to be overexpressed in several cancers. To allow the probing and modulation of dCK activity, a new class of small-molecule inhibitors of the enzyme were developed. Here, the structural characterization of four of these inhibitors in complex with human dCK is presented. The structures reveal that the compounds occupy the nucleoside-binding site and bind to the open form of dCK. Surprisingly, a slight variation in the nature of the substituent at the 5-position of the thiazole ring governs whether the active site of the enzyme is occupied by one or two inhibitor molecules. Moreover, this substituent plays a critical role in determining the affinity, improving it from >700 to 1.5 nM in the best binder. These structures lay the groundwork for future modifications that would result in even tighter binding and the correct placement of moieties that confer favorable pharmacodynamics and pharmacokinetic properties.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Nomme
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Natasha D
authors.initials: ND
authors.lastname: Sansone
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Armijo
authors.affiliation: Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Olson
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Caius
authors.initials: C
authors.lastname: Radu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Arnon
authors.initials: A
authors.lastname: Lavie
mesh_terms: D018360:Crystallography, X-Ray; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D014530:Uridine Diphosphate; D003842:Deoxycytidine Kinase
keywords: deoxycytidine kinase; inhibitors; nucleotide salvage pathway