News & Events
News & Events

New Publication: Targeting Drug-Resistant GIST with Covalent Inhibitors

We are excited to announce our latest research publication in the Journal of Medicinal Chemistry! We developed novel covalent inhibitors targeting mutant versions of KIT and PDGFRA.

Why does this matter?

Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the digestive tract, are driven by activating mutations in the KIT and PDGFRA genes. While tyrosine kinase inhibitors (TKIs) have revolutionized treatment, drug resistance, and side effects remain major challenges. In this work, we developed covalent TKIs targeting KIT and PDGFRA drug-resistance mutations. Using a combination of structure-based drug design, organic synthesis, and biological evaluation, we identified promising inhibitors that effectively target mutant versions of these driver oncogenes. Most notably, we report the first crystal structure of PDGFRA bound to a covalent inhibitor, providing key insights into how these small molecules interact with their targets. Our findings highlight the promise of covalent inhibitors to overcome drug resistance and advance safer, more effective therapies for advanced GIST.

Read the full paper here: https://doi.org/10.1021/acs.jmedchem.4c02472

 

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