Research ArticleCancer

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors

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Science Translational Medicine  29 Apr 2020:
Vol. 12, Issue 541, eaaz2481
DOI: 10.1126/scitranslmed.aaz2481

Getting the GIST of treatment

Gastrointestinal stromal tumor, or GIST, can be targeted by inhibiting KIT and platelet-derived growth factor α (PDGFRα). Unfortunately, the therapeutic effects do not always last, as the tumors develop resistance mutations that are not susceptible to existing drugs. Banks et al. report the design of AZD3229, a compound that combines selectivity for KIT and PDGFRα with broad activity against a variety of disease-causing mutations. Its selectivity decreases the risk of off-target toxicity, which has been a problem for multiple other KIT/PDGFRα inhibitors. AZD3229 showed promising activity and safety in a range of drug-resistant GIST mouse models, suggesting its potential for clinical translation.

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