{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:16:09Z","timestamp":1790270169333,"version":"4.1.0"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"22","license":[{"start":{"date-parts":[[2015,10,23]],"date-time":"2015-10-23T00:00:00Z","timestamp":1445558400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EB013685"],"award-info":[{"award-number":["EB013685"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["5U54 CA119347"],"award-info":[{"award-number":["5U54 CA119347"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50 CA86306"],"award-info":[{"award-number":["P50 CA86306"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006224","name":"Argonne National Laboratory, Office of Science","doi-asserted-by":"publisher","award":["DE-AC02- 06CH11357"],"award-info":[{"award-number":["DE-AC02- 06CH11357"]}],"id":[{"id":"10.13039\/100006224","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has &amp;gt;60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.<\/jats:p>","DOI":"10.1021\/jm501124j","type":"journal-article","created":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T16:21:47Z","timestamp":1414081307000},"page":"9480-9494","source":"Crossref","is-referenced-by-count":16,"title":["Structure-Guided Development\nof Deoxycytidine Kinase\nInhibitors with Nanomolar Affinity and Improved Metabolic Stability"],"prefix":"10.1021","volume":"57","author":[{"given":"Julian","family":"Nomme","sequence":"first","affiliation":[{"name":"University of Illinois at Chicago , and , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond M.","family":"Gipson","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Armijo","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuc","family":"Le","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Poddar","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Smith","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard D.","family":"Santarsiero","sequence":"additional","affiliation":[{"name":"University of Illinois at Chicago , and , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hien-Anh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"University of Illinois at Chicago , and , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Czernin","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastassia N.","family":"Alexandrova","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Jung","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caius G.","family":"Radu","sequence":"additional","affiliation":[{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California\u2500 Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Lavie","sequence":"additional","affiliation":[{"name":"University of Illinois at Chicago , and , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,10,23]]},"reference":[{"key":"2026090121152297000_cit1","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00018-002-8511-x","article-title":"Structure and function\nof cellular deoxyribonucleoside kinases","volume":"59","author":"Eriksson","year":"2002","journal-title":"Cell.\nMol. Life Sci."},{"key":"2026090121152297000_cit2","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nsb942","article-title":"Structure of human\ndCK suggests strategies to improve anticancer and antiviral therapy","volume":"10","author":"Sabini","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"2026090121152297000_cit3","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1073\/pnas.0913900107","article-title":"Requirement for deoxycytidine kinase in T and B lymphocyte\ndevelopment","volume":"107","author":"Toy","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090121152297000_cit4","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1084\/jem.20121061","article-title":"Nucleoside salvage pathway kinases\nregulate hematopoiesis by linking nucleotide metabolism with replication\nstress","volume":"209","author":"Austin","year":"2012","journal-title":"J. Exp. Med."},{"key":"2026090121152297000_cit5","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.4049\/jimmunol.1102587","article-title":"A deficiency\nin nucleoside salvage impairs murine lymphocyte development, homeostasis,\nand survival","volume":"188","author":"Choi","year":"2012","journal-title":"J. Immunol."},{"key":"2026090121152297000_cit6","doi-asserted-by":"crossref","first-page":"9621","DOI":"10.1093\/nar\/gks707","article-title":"Deoxycytidine kinase\nregulates the\nG2\/M checkpoint through interaction with cyclin-dependent kinase 1\nin response to DNA damage","volume":"40","author":"Yang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2026090121152297000_cit7","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.20131738","article-title":"Co-targeting of convergent nucleotide biosynthetic\npathways for leukemia eradication","volume":"211","author":"Nathanson","year":"2014","journal-title":"J. Exp. 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Crystallogr."},{"key":"2026090121152297000_cit10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1021\/bi0518646","article-title":"Structural basis for\nthe preference of UTP over ATP in human deoxycytidine kinase: illuminating\nthe role of main-chain reorganization","volume":"45","author":"Godsey","year":"2006","journal-title":"Biochemistry"},{"key":"2026090121152297000_cit11","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jmb.2008.02.061","article-title":"Structural\nbasis for substrate promiscuity of dCK","volume":"378","author":"Sabini","year":"2008","journal-title":"J. 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Chem."},{"key":"2026090121152297000_cit23","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S0076-6879(78)51066-5","article-title":"Guanylate kinases\nfrom human erythrocytes, hog brain, and rat liver","volume":"51","author":"Agarwal","year":"1978","journal-title":"Methods Enzymol."},{"key":"2026090121152297000_cit24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0169-2607(86)90062-3","article-title":"MULTI-FORTE,\na microcomputer program for modelling and simulation of pharmacokinetic\ndata","volume":"23","author":"Bourne","year":"1986","journal-title":"Comput. Methods Programs Biomed."},{"key":"2026090121152297000_cit25","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0169-2607(89)90129-6","article-title":"BOOMER,\na simulation and modeling program for pharmacokinetic and pharmacodynamic\ndata analysis","volume":"29","author":"Bourne","year":"1989","journal-title":"Comput. 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