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

by Selleckchem | Aug 26 2023

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.

Comments:

Thank you for providing the information about AZD3229, a potential small-molecule inhibitor for the treatment of gastrointestinal stromal tumor (GIST). Based on the details you provided, AZD3229 appears to be a promising drug candidate with several favorable characteristics.

GIST is a type of sarcoma, and the most common driver mutations in GIST are found in the KIT or platelet-derived growth factor α (PDGFRα) genes. While imatinib, a first-line treatment, has significantly improved GIST management, many patients develop drug resistance due to the acquisition of secondary mutations in KIT/PDGFRα. Second- and third-line treatments such as sunitinib and regorafenib have limited efficacy against these mutations, often resulting in disease progression within a few months. Additionally, these drugs can cause high-grade hypertension by inhibiting vascular endothelial growth factor receptor 2 (VEGFR2).

AZD3229, on the other hand, is a potent and selective small-molecule inhibitor specifically designed to target a broad range of primary and imatinib-resistant secondary mutations seen in GIST, affecting KIT and PDGFRα. In preclinical studies using engineered cell lines and GIST-derived cell lines, AZD3229 demonstrated 15 to 60 times greater potency than imatinib in inhibiting primary KIT mutations. It also exhibited low nanomolar activity against a wide spectrum of secondary mutations. These findings suggest that AZD3229 could effectively target and inhibit GIST with various genetic alterations.

Furthermore, AZD3229 showed durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions. Importantly, the doses used in these studies did not cause changes in arterial blood pressure, as observed in rat telemetry studies. This indicates that AZD3229 may have a more favorable tolerability profile compared to existing standard-of-care agents (imatinib, sunitinib, and regorafenib), as well as other investigational drugs like avapritinib (BLU-285) and ripretinib (DCC-2618).

Based on its superior potency, selectivity, and potential to target clinically relevant KIT/PDGFRα mutations in GIST, AZD3229 has the potential to become a best-in-class inhibitor for this disease. However, it's important to note that the information you provided seems to be part of a research report or a scientific article, and it's essential to consult the most recent and comprehensive clinical data to assess the current status of AZD3229's development and its potential as a therapeutic option for GIST.