845889-22-7Relevant academic research and scientific papers
Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N- (piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas
Oza, Vibha,Ashwell, Susan,Almeida, Lynsie,Brassil, Patrick,Breed, Jason,Deng, Chun,Gero, Thomas,Grondine, Michael,Horn, Candice,Ioannidis, Stephanos,Liu, Dongfang,Lyne, Paul,Newcombe, Nicholas,Pass, Martin,Read, Jon,Ready, Shannon,Rowsell, Sian,Su, Mei,Toader, Dorin,Vasbinder, Melissa,Yu, Dingwei,Yu, Yan,Xue, Yafeng,Zabludoff, Sonya,Janetka, James
experimental part, p. 5130 - 5142 (2012/09/07)
Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.
Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors
Janetka, James W.,Almeida, Lynsie,Ashwell, Susan,Brassil, Patrick J.,Daly, Kevin,Deng, Chun,Gero, Thomas,Glynn, Roberta E.,Horn, Candice L.,Ioannidis, Stephanos,Lyne, Paul,Newcombe, Nicholas J.,Oza, Vibha B.,Pass, Martin,Springer, Stephanie K.,Su, Mei,Toader, Dorin,Vasbinder, Melissa M.,Yu, Dingwei,Yu, Yan,Zabludoff, Sonya D.
scheme or table, p. 4242 - 4248 (2009/04/10)
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.
SUBSTITUTED HETEROCYCLES AND THE USES THEREOF
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Page/Page column 70, (2010/02/12)
This invention relates to novel compounds having the structural formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of cancer.
