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 Thiophenecarbox

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• 作者：Vibha Oza ; Susan Ashwell ; Lynsie Almeida ; Patrick Brassil ; Jason Breed ; Chun Deng ; Thomas Gero ; Michael Grondine ; Candice Horn ; Stephanos Ioannidis ; Dongfang Liu ; Paul Lyne ; Nicholas Newcombe ; Martin Pass ; Jon Read ; Shannon Ready ; Si芒n Rowsell ; Mei Su ; Dorin Toader ; Melissa Vasbinder ; Dingwei Yu ; Yan Yu ; Yafeng Xue ; Sonya Zabludoff ; James Janetka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5130-5142
• 全文大小：491K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

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鈥?b>3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKK尾, 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.