极光激酶
极光抑制剂
极光激酶B
化学
激酶
铅化合物
配体效率
极光A激酶
吡唑
酪氨酸激酶
有丝分裂
体内
药物发现
体外
癌症研究
生物化学
配体(生物化学)
细胞生物学
立体化学
细胞周期
信号转导
生物
细胞分裂
主轴装置
细胞
遗传学
受体
作者
Steven Howard,Valério Berdini,John A. Boulstridge,Maria G. Carr,David M. Cross,Jayne Curry,Lindsay A. Devine,Theresa R. Early,Lynsey Fazal,Adrian L. Gill,Michelle L. Heathcote,Sarita Maman,Julia E. Matthews,Rachel McMenamin,Eva F. Navarro,Michael A. O’Brien,Marc O’Reilly,David C. Rees,Matthias Reule,Dominic Tisi,Glyn Williams,M. Vinković,Paul G. Wyatt
摘要
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
科研通智能强力驱动
Strongly Powered by AbleSci AI