Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors.
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.
Jessop
Theodore C
TC
Lexicon Pharmaceuticals, Princeton, NJ 08540, United States. tjessop@lexpharma.com
Tarver
James E
JE
Carlsen
Marianne
M
Xu
Amy
A
Healy
Jason P
JP
Heim-Riether
Alexander
A
Fu
Qinghong
Q
Taylor
Jerry A
JA
Augeri
David J
DJ
Shen
Min
M
Stouch
Terry R
TR
Swanson
Ronald V
RV
Tari
Leslie W
LW
Hunter
Michael
M
Hoffman
Isaac
I
Keyes
Philip E
PE
Yu
Xuan-Chuan
XC
Miranda
Maricar
M
Liu
Qingyun
Q
Swaffield
Jonathan C
JC
David Kimball
S
S
Nouraldeen
Amr
A
Wilson
Alan G E
AG
Foushee
Ann Marie Digeorge
AM
Jhaver
Kanchan
K
Finch
Rick
R
Anderson
Steve
S
Oravecz
Tamas
T
Carson
Kenneth G
KG
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
D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; C007746:5-fluoro-2'-deoxycytidine