Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors.
Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.
Janetka
James W
JW
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. james.janetka@astrazeneca.com
Almeida
Lynsie
L
Ashwell
Susan
S
Brassil
Patrick J
PJ
Daly
Kevin
K
Deng
Chun
C
Gero
Thomas
T
Glynn
Roberta E
RE
Horn
Candice L
CL
Ioannidis
Stephanos
S
Lyne
Paul
P
Newcombe
Nicholas J
NJ
Oza
Vibha B
VB
Pass
Martin
M
Springer
Stephanie K
SK
Su
Mei
M
Toader
Dorin
D
Vasbinder
Melissa M
MM
Yu
Dingwei
D
Yu
Yan
Y
Zabludoff
Sonya D
SD
D000577:Amides / Q000737:chemistry; D017209:Apoptosis; D002244:Carbon / Q000737:chemistry; D002453:Cell Cycle; D000071877:Checkpoint Kinase 1; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004249:DNA Damage; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010647:Phenyl Ethers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry; D014508:Urea / Q000737:chemistry
D000577:Amides; D010647:Phenyl Ethers; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D002244:Carbon; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1