NVP-AUY922: A novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis
NVP-AUY922: A novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis
复制标题
DOI：
10.1158/0008-5472.can-07-5256
复制
发表时间：
2008-04-15
期刊：
影响因子：
11.2
通讯作者：
Workman, Paul
中科院分区：
文献类型：
--
作者：
Eccles, Suzanne A.;Massey, Andy;Workman, Paul
我们描述了NVP-AUY 922，一种新的间苯二酚异恶唑酰胺热休克蛋白90（HSP 90）抑制剂的生物学特性。NVP-AUY 922有效抑制HSP 90（Kd = 1.7 nmol/L）和人肿瘤细胞的增殖，GI（50）值约为2 - 40 nmol/L，诱导G（1）-G（2）阻滞和凋亡。活性独立于NQO 1/DT-心肌黄酶，在耐药细胞和缺氧条件下维持。HSP 90抑制的分子特征，包括诱导的HSP 72和耗尽的客户蛋白，是容易证明的。NVP-AUY 922的葡萄糖醛酸化程度低于之前描述的异恶唑，从而在人类癌细胞和异种移植物中产生更高的药物水平。NVP-AUY 922（50 mg/kg i.p.或i.v.）无胸腺小鼠产生的峰值肿瘤水平至少比细胞GI高100倍（50）。这在具有不同致癌特征的人肿瘤异种移植物中产生了统计学显著的生长抑制和/或消退：BT474乳腺肿瘤治疗/对照，21%; A2780卵巢，11%; U87 MG胶质母细胞瘤，7%; PC 3前列腺，37%;和WM 266.4黑色素瘤，31%。治疗效果与药效学标志物的变化一致，包括诱导HSP 72和消耗ERBB 2，CRAF，细胞周期蛋白依赖性激酶4，磷酸化AKT/总AKT和缺氧诱导因子-1 α，通过Western印迹，电化学发光免疫测定或免疫组织化学测定。NVP-AUY 922还显著抑制体外肿瘤细胞趋化性/侵袭、WM 266.4黑色素瘤肺转移和原位植入的PC 3LN 3前列腺癌的淋巴转移。NVP-AUY 922抑制人内皮细胞的增殖、化学迁移和肾小管分化，并且抗血管生成活性反映在肿瘤异种移植物中微血管密度降低。总的来说，数据表明NVP-AUY 922是一种有效的新型HSP 90抑制剂，通过几个过程（细胞抑制、凋亡、侵袭和血管生成）起作用以抑制肿瘤生长和转移。NVP-AUY 922已进入I期临床试验。
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K-d = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1 alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.