Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors
Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors
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DOI：
10.1126/scitranslmed.aaz2481
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发表时间：
2020-04-29
影响因子：
17.1
通讯作者：
Anjum, Rana
中科院分区：
文献类型：
--
作者：
Banks, Erica;Grondine, Michael;Anjum, Rana
胃肠道间质瘤（GIST）是由KIT或血小板衍生生长因子突变驱动的最常见的人类肉瘤。（PDGFR α）。尽管一线治疗伊马替尼彻底改变了GIST治疗，但由于获得继发性KIT/PDGFR α突变而导致的耐药性在大多数患者中发展。二线和三线治疗，舒尼替尼和瑞格非尼，缺乏对GIST中KIT/PDGFR α突变过多的活性，疾病进展的中位时间为4至6个月，抑制血管内皮生长因子受体2（VEGFR 2）引起高度高血压。GIST患者对耐受性良好的药物存在未满足的需求，该药物可强效抑制一系列KIT/PDGFR α突变。在这里，我们报告了AZD 3229的发现和药理学特征，AZD 3229是一种强效和选择性的KIT和PDGFR α小分子抑制剂，旨在抑制GIST中观察到的广泛的原发性和伊马替尼耐药继发性突变。在工程和GIST衍生细胞系中，AZD 3229在抑制KIT原发突变方面的效力是伊马替尼的15至60倍，并且对广泛的继发突变具有低纳摩尔活性。在大鼠遥测研究中，AZD 3229在患者源性异种移植（PDX）GIST模型中对KIT信号传导产生持久抑制，在动脉血压（BP）无变化的剂量下导致肿瘤消退。AZD 3229的效价和选择性优于标准治疗（SoC）药物-伊马替尼、舒尼替尼和瑞格非尼，以及试验药物avapritinib（BLU-285）和Ripretinib（DCC-2618）。AZD 3229有可能成为GIST中临床相关KIT/PDGFR α突变的同类最佳抑制剂。
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor. (PDGFR alpha). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFR alpha mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFR alpha 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/PDGFR alpha mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFR alpha 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/PDGFR alpha mutations in GIST.