Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors

基诺美 化学 药效团 酪氨酸激酶 达沙替尼 药理学 铅化合物 激酶 结构-活动关系 生物化学 信号转导 体外 生物
作者
Jason G. Kettle,Rana Anjum,Evan Barry,Deepa Bhavsar,Crystal Brown,Scott Boyd,Andrew D. Campbell,Kristin Goldberg,Michael Grondine,Sylvie M. Guichard,Christopher J. Hardy,Thomas A. Hunt,Rhys D.O. Jones,Xiuwei Li,O. Moleva,D. Ogg,R. Overman,Martin J. Packer,Stuart E. Pearson,Marianne Schimpl
出处
期刊:Journal of Medicinal Chemistry [American Chemical Society]
卷期号:61 (19): 8797-8810 被引量:50
标识
DOI:10.1021/acs.jmedchem.8b00938
摘要

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.
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