Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

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• 作者：Wei-Sheng Huang ; Shuangying Liu ; Dong Zou ; Mathew Thomas ; Yihan Wang ; Tianjun Zhou ; Jan Romero ; Anna Kohlmann ; Feng Li ; Jiwei Qi ; Lisi Cai ; Timothy A. Dwight ; Yongjin Xu ; Rongsong Xu ; Rory Dodd ; Angela Toms ; Lois Parillon ; Xiaohui Lu ; Rana Anjum ; Sen Zhang ; Frank Wang ; Jeffrey Keats ; Scott D. Wardwell ; Yaoyu Ning ; Qihong Xu ; Lauren E. Moran ; Qurish K. Mohemmad ; Hyun Gyung Jang ; Tim Clackson ; Narayana I. Narasimhan ; Victor M. Rivera ; Xiaotian Zhu ; David Dalgarno ; William C. Shakespeare
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4948-4964
• 全文大小：683K
• 年卷期：0
• ISSN：1520-4804

文摘

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC₅₀s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.