Open AccessStructural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity‐determining moieties of the molecules
Author(s) -
Nomme Julian,
Murphy Jennifer M.,
Su Ying,
Sansone Natasha D.,
Armijo Amanda L.,
Olson Steven T.,
Radu Caius,
Lavie Ar
Publication year - 2014
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s1399004713025030
Subject(s) - deoxycytidine kinase , prodrug , substituent , thiazole , chemistry , small molecule , nucleoside , enzyme , stereochemistry , nucleoside analogue , structure–activity relationship , biochemistry , combinatorial chemistry , deoxycytidine , in vitro , biology , cancer , genetics , gemcitabine
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 n M 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.