1407520-11-9Relevant articles and documents
Novel aminopyrimidine EGFR inhibitor
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Paragraph 0247-0253, (2021/03/24)
The present invention provides a novel aminopyrimidine compound that is a selective inhibitor of the fourth generation EGFR (T790M/C797S mutation), a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound, and
Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase
Huang, Wei-Sheng,Liu, Shuangying,Zou, Dong,Thomas, Mathew,Wang, Yihan,Zhou, Tianjun,Romero, Jan,Kohlmann, Anna,Li, Feng,Qi, Jiwei,Cai, Lisi,Dwight, Timothy A.,Xu, Yongjin,Xu, Rongsong,Dodd, Rory,Toms, Angela,Parillon, Lois,Lu, Xiaohui,Anjum, Rana,Zhang, Sen,Wang, Frank,Keats, Jeffrey,Wardwell, Scott D.,Ning, Yaoyu,Xu, Qihong,Moran, Lauren E.,Mohemmad, Qurish K.,Jang, Hyun Gyung,Clackson, Tim,Narasimhan, Narayana I.,Rivera, Victor M.,Zhu, Xiaotian,Dalgarno, David,Shakespeare, William C.
, p. 4948 - 4964 (2016/06/13)
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.
COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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Page/Page column 48, (2012/11/14)
The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula (I), wherein the variables are as defined herein.