Design, Synthesis, and SAR of Covalent KIT and PDGFRA InhibitorsExploring Their Potential in Targeting GIST

Gastrointestinal stromal tumors (GIST), driven by KIT
and PDGFRA
mutations, are the most common mesenchymal tumors of the gastrointestinal
tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment,
resistance mutations and off-target toxicity limit their efficacy.
This study develops covalent TKIs targeting drug-resistant GIST through
structure-based design, synthesis, and biological evaluation. SAR
studies provided key insights into mutant KIT and PDGFRA interactions,
and the first crystal structure of PDGFRA bound to a covalent inhibitor
is reported. These findings highlight the promise of covalent inhibitors
for overcoming resistance and advancing safer, more effective therapies
for advanced GIST.