title: Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors.
abstract: A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.
authors.affiliation: Lexicon Pharmaceuticals, Princeton, NJ 08540, United States. tjessop@lexpharma.com
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Jessop
authors.forename: James E
authors.initials: JE
authors.lastname: Tarver
authors.forename: Marianne
authors.initials: M
authors.lastname: Carlsen
authors.forename: Amy
authors.initials: A
authors.lastname: Xu
authors.forename: Jason P
authors.initials: JP
authors.lastname: Healy
authors.forename: Alexander
authors.initials: A
authors.lastname: Heim-Riether
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Fu
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Taylor
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Terry R
authors.initials: TR
authors.lastname: Stouch
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
authors.forename: Michael
authors.initials: M
authors.lastname: Hunter
authors.forename: Isaac
authors.initials: I
authors.lastname: Hoffman
authors.forename: Philip E
authors.initials: PE
authors.lastname: Keyes
authors.forename: Xuan-Chuan
authors.initials: XC
authors.lastname: Yu
authors.forename: Maricar
authors.initials: M
authors.lastname: Miranda
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Swaffield
authors.forename: S
authors.initials: S
authors.lastname: David Kimball
authors.forename: Amr
authors.initials: A
authors.lastname: Nouraldeen
authors.forename: Alan G E
authors.initials: AG
authors.lastname: Wilson
authors.forename: Ann Marie Digeorge
authors.initials: AM
authors.lastname: Foushee
authors.forename: Kanchan
authors.initials: K
authors.lastname: Jhaver
authors.forename: Rick
authors.initials: R
authors.lastname: Finch
authors.forename: Steve
authors.initials: S
authors.lastname: Anderson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Carson
mesh_terms: D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; C007746:5-fluoro-2'-deoxycytidine