Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)
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- 作者：Shyh-Ming Yang ; Adam Yasgar ; Bettina Miller ; Madhu Lal-Nag ; Kyle Brimacombe ; Xin Hu ; Hongmao Sun ; Amy Wang ; Xin Xu ; Kimloan Nguyen ; Udo Oppermann ; Marc Ferrer ; Vasilis Vasiliou ; Anton Simeonov ; Ajit Jadhav ; David J. Maloney
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：58
- 期：15
- 页码：5967-5978
- 全文大小：535K
- ISSN：1520-4804
文摘
Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17尾4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.