Discovery of Conformational Control Inhibitors Switching off the Activated c‑KIT and Targeting a Broad Range of Clinically Relevant c‑KIT Mutants

Drug
resistance due to acquired mutations that constitutively activate
c-KIT is a significant challenge in the treatment of patients with
gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)­pyrimidin-4-ylamino]-thiazol-5-yl}­phenyl)­urea
(10a) as a potent inhibitor against unactivated and activated
c-KIT. The binding of 10a induced rearrangements of the
DFG motif, αC-helix, juxtamembrane domain, and the activation
loop to switch the activated c-KIT back to its structurally inactive
state. To the best of our knowledge, it is the first structural evidence
demonstrating how a compound can inhibit the activated c-KIT by switching
back to its inactive state through a sequence of conformational changes.
Moreover, 10a can effectively inhibit various c-KIT mutants
and the proliferation of several GIST cell lines. The distinct binding
features and superior inhibitory potency of 10a, together
with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced
GISTs.