1. 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
- Author
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Siân Rowsell, Shannon Ready, James W. Janetka, Dongfang Liu, Paul Lyne, Jason Breed, Patrick Brassil, Nicholas John Newcombe, Jon Read, Susan Ashwell, Dingwei Yu, Mei Su, Dorin Toader, Yan Yu, Melissa Vasbinder, Vibha Oza, Lynsie Almeida, Chun Deng, Sonya Zabludoff, Martin Pass, Stephanos Ioannidis, Candice Horn, Michael Grondine, Thomas Gero, and Yafeng Xue
- Subjects
Models, Molecular ,animal structures ,DNA repair ,Stereochemistry ,DNA damage ,medicine.drug_class ,High-throughput screening ,Carboxamide ,Antineoplastic Agents ,Thiophenes ,Crystallography, X-Ray ,Irinotecan ,environment and public health ,Deoxycytidine ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Ribose ,medicine ,Structure–activity relationship ,Animals ,Urea ,CHEK1 ,Protein Kinase Inhibitors ,Binding Sites ,Molecular Structure ,Chemistry ,Kinase ,Drug Synergism ,Stereoisomerism ,Xenograft Model Antitumor Assays ,Gemcitabine ,High-Throughput Screening Assays ,Rats ,enzymes and coenzymes (carbohydrates) ,Drug Design ,Checkpoint Kinase 1 ,Molecular Medicine ,Camptothecin ,biological phenomena, cell phenomena, and immunity ,Protein Kinases ,DNA Damage - Abstract
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.
- Published
- 2012