Discovery of a Potent, Orally Bioavailable Small-Molecule Inhibitor of Wildtype KIT with Exceptionally High Kinome Selectivity.

Mast cells play critical roles in the pathogenesis of many allergic and inflammatory diseases. KIT, a receptor tyrosine kinase, is a crucial regulator of mast cells and, in consequence, the modulation of mast cells through KIT inhibition presents a promising therapeutic approach for treating a range of chronic diseases. Clinical applications of small-molecule KIT inhibitors have been limited to oncology due to adverse effects associated with poor kinome selectivity. Here, we describe a highly selective small-molecule KIT inhibitor (7) that exhibits excellent broad kinome selectivity, with a selectivity score of S(50%) = 0.003. Data-driven investigations of structure-activity relationships and careful modulation of physicochemical properties yielded improvements in potency, selectivity, and metabolic stability. Compound 7 demonstrated promising in vivo therapeutic efficacy in an SCF-driven acute cutaneous anaphylaxis model in rodents.