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

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.

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

“…Engineered cell lines including Ba/F3 have been shown previously to faithfully mimic clinical efficacy of various agents in GIST. 43 into a c-KIT scaffold promoted formation of a covalent interaction with the target where acrylamide had previously failed, confirmed by X-ray structure determination. This scaffold was also found to be highly potent against PDGFR with a suggested covalent mode of action and demonstrated potent cell activity with fewer off target effects than the corresponding acrylamide.…”

“…The C-helices of the two kinases also have different residues at their termini, altering the size and shape of the pockets; with resultant variation in the affinity of ligands. 43 Compound 24 was a compound originally synthesized in an in-house project to target the kinase PDGFR, shown to have affinity for c-KIT and whose binding mode was later solved in both c-KIT and KDR crystal structures. 44 From these it was evident that the basic side chain pointed towards Cys788 in c-KIT and thus could act as a handle for addition of a cysteine reactive warhead.…”

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

“…A docking study between AIU2001 and FLT3 (PDB code: 4XUF) or c-KIT (PDB code: 6GQJ) was performed using the X-ray structures [16,17]. Pi interactions were identified between the benzyl group of AIU2001 and the Tyr693 of FLT3, and the naphthyl group of AIU2001 and both Phe691 and Phe830.…”

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…Kettle et al 63 discovered that the quinazoline-triazole conjugate 20 (Fig. 4) is a potential Pan-KIT mutant inhibitor towards gastrointestinal stromal tumours.…”