Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
复制标题
I类磷脂酰肌醇3-激酶的有效抑制剂的生物学特性：从PI-103到PI-540，PI-620到口服剂GDC-0941。
DOI：
10.1158/1535-7163.mct-08-1200
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发表时间：
2009-07
影响因子：
5.7
通讯作者：
Workman P
中科院分区：
文献类型：
--
作者：
Raynaud FI;Eccles SA;Patel S;Alix S;Box G;Chuckowree I;Folkes A;Gowan S;De Haven Brandon A;Di Stefano F;Hayes A;Henley AT;Lensun L;Pergl-Wilson G;Robson A;Saghir N;Zhyvoloup A;McDonald E;Sheldrake P;Shuttleworth S;Valenti M;Wan NC;Clarke PA;Workman P
磷脂酰肌醇 3-激酶通路在人类癌症中经常失调，抑制剂提供了相当大的治疗潜力。我们之前描述了有前途的三环吡啶并呋喃嘧啶先导化合物和化学工具化合物 PI-103。我们现在报告药物优化的双环噻吩并嘧啶衍生物 PI-540 和 PI-620 以及由此产生的临床开发候选药物 GDC-0941 的特性。所有四种化合物均抑制磷脂酰肌醇 3-激酶 p110α，IC50 ≤ 10 nmol/L。尽管异构体选择性存在一些差异，这些药物在一组人类癌细胞系中表现出与 PI-103 相似的体外抗增殖特性，在 PTEN 阴性 U87MG 人类胶质母细胞瘤细胞中具有亚微摩尔效力，并且具有相当的磷脂酰肌醇 3 激酶途径调节作用。 PI-540 和 PI-620 在小鼠体内表现出溶解度和代谢的改善以及高组织分布。腹腔注射后，两种化合物均比 PI-103 具有更好的抗肿瘤功效。在无胸腺小鼠的 U87MG 胶质母细胞瘤肿瘤异种移植物中给药，PI-540（50 mg/kg b.i.d.）和 PI-620（25 mg/kg b.i.d.）的治疗/对照值分别为 34%（66% 抑制）和 27%（73% 抑制）。 GDC-0941 显示出与 PI-103、PI-540 和 PI-620 相当的体外抗肿瘤活性，并且在小鼠中显示出 78% 的口服生物利用度，口服 150 mg/kg 后，肿瘤暴露超过 50% 抗增殖浓度超过 8 小时。并持续抑制磷脂酰肌醇 3-激酶途径。这些特性导致了优异的剂量依赖性口服抗肿瘤活性，每日口服。 150 mg/kg 的剂量对 U87MG 胶质母细胞瘤和 IGROV-1 卵巢癌异种移植物的生长抑制率分别为 98% 和 80%。总之，这些数据支持 GDC-0941 作为一种有效的、口服生物可利用的磷脂酰肌醇 3-激酶抑制剂的开发。 GDC-0941最近已进入I期临床试验。
The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110α with IC50 ≤ 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% anti-proliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.