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 occupie

SUBMITTER: Nomme J 

PROVIDER: S-EPMC3919262 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature