| Autor: |
Banks, Erica, Grondine, Michael, Bhavsar, Deepa, Barry, Evan, Kettle, Jason G., Reddy, Venkatesh Pilla, Brown, Crystal, Wang, Haiyun, Mettetal, Jerome T., Collins, Teresa, Adeyemi, Oladipupo, Overman, Ross, Lawson, Deborah, Harmer, Alexander R., Reimer, Corinne, Drew, Lisa, Packer, Martin J., Cosulich, Sabina, Jones, Rhys DO., Shao, Wenlin |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 4/29/2020, Vol. 12 Issue 541, p1-13, 13p |
| Abstrakt: |
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. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents—imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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