Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven...

Area of Science:

• Oncology
• Medicinal Chemistry
• Structural Biology

Background:

• Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract.
• Current tyrosine kinase inhibitors (TKIs) for GIST face challenges with off-target toxicities and acquired drug resistance mutations.
• Existing TKIs often exhibit limited efficacy against resistance mutations due to their binding motifs.

Purpose of the Study:

• To design novel kinase inhibitors with selectivity for mutant KIT and PDGFRA, overcoming resistance mechanisms in GIST.
• To define molecular interactions driving resistance and inhibitor selectivity through structure-activity relationship (SAR) studies.
• To develop potent and selective inhibitors for interrogating GIST resistance pathways.

Main Methods:

• Employed a structure-based scaffold-hopping strategy to design novel kinase inhibitors.
• Conducted extensive structure-activity relationship (SAR) studies.
• Determined 14 co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, to guide inhibitor design.

Main Results:

• Developed lead 6,7-quinazoline-based inhibitors demonstrating high potency against clinically relevant KIT/PDGFRA mutations.
• Demonstrated effective suppression of downstream signaling pathways by the novel inhibitors.
• Elucidated the molecular basis for targeting solvent-front mutations, including PDGFRA-G680R, across oncogenic kinases.

Conclusions:

• The designed quinazoline-based inhibitors offer a promising therapeutic strategy for GIST, particularly in cases of drug resistance.
• These compounds serve as valuable chemical tools for further research into GIST resistance mechanisms.
• The structural insights gained provide a foundation for targeting solvent-front mutations in other oncogenic kinases.