Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven drug-resistance in GIST

Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes in gastrointestinal stromal tumors (GIST), a type of mesenchymal tumor. However, the development of drug-resistant mutations remains a significant challenge in GIST treatment. The authors of this study developed a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. This approach was based on structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation. The researchers defined key molecular interactions underlying resistance and inhibitor selectivity in their lead 6,7-quinazoline-based inhibitors. These compounds showed high potency against clinically relevant KIT/PDGFRA mutations and effectively suppressed downstream signaling. The study's findings provide selective chemical tools to interrogate resistance mechanisms and highlight the molecular basis for targeting solvent-front mutations across oncogenic kinases.