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Discovery of N -(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H -1,2,3-triazol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors

DOI: 10.1021/acs.jmedchem.8b00938 DOI Help

Authors: Jason G. Kettle (AstraZeneca) , Rana Anjum (AstraZeneca) , Evan Barry (AstraZeneca) , Deepa Bhavsar (AstraZeneca) , Crystal Brown (AstraZeneca) , Scott Boyd (AstraZeneca) , Andrew Campbell (AstraZeneca) , Kristin Goldberg (AstraZeneca) , Michael Grondine (AstraZeneca) , Sylvie Guichard (AstraZeneca) , Christopher J. Hardy (AstraZeneca) , Tom Hunt (AstraZeneca) , Rhys D. O. Jones (AstraZeneca) , Xiuwei Li (Pharmaron Beijing Co., Ltd) , Olga Moleva (AstraZeneca) , Derek Ogg (AstraZeneca) , Ross C. Overman (AstraZeneca) , Martin J. Packer (AstraZeneca) , Stuart Pearson (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Wenlin Shao (AstraZeneca) , Aaron Smith (AstraZeneca) , James M. Smith (AstraZeneca) , Darren Stead (AstraZeneca) , Steve Stokes (AstraZeneca) , Michael Tucker (AstraZeneca) , Yang Ye (Pharmaron Beijing Co., Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 12419 , 14631

Abstract: 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.

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

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