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Purpose:The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.Experimental Design:A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines.Results:AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.Conclusions:We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.

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.

More evidence is required to endorse the 1-step approach for gestational diabetes mellitus (GDM) for clinical practice. Since 2010, our department has pragmatically allowed faculty to self-select the guidelines they use to screen and diagnose GDM. We sought to compare the maternal and neonatal outcomes from these two simultaneous cohorts.We performed a retrospective cohort study of all singleton pregnancies delivered between October 2011 and -November 2013 at our hospital. Patients were excluded if they had preexisting diabetes, were not screened or screened inappropriately, or their fetus had congenital anomalies. Patients were grouped by their screening strategy, and maternal and neonatal outcomes were analyzed.The 1-step group had a higher incidence of GDM (21.6% versus 5.0%). Initial results suggested higher rates of neonatal hypoglycemia, phototherapy for hyperbilirubinemia, and a lower rate of gestational HTN. After adjustment, these differences disappeared, but a lower rate of large for gestational age (LGA) infants was discovered (adjusted odds ratios (aOR) 0.78).The picture remains unclear as to whether the 1-step approach is associated with significantly improved outcomes compared with the 2-step approach. We did find a lower risk for a LGA infant in our 1-step cohort, but it is unlikely that the 1-step approach would be cost-effective due to the absence of other improved outcomes.