新型强效 AKT 抑制剂 CCT128930 的临床前药理学、抗肿瘤活性和药效学标志物的开发,Molecular Cancer Therapeutics

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新型强效 AKT 抑制剂 CCT128930 的临床前药理学、抗肿瘤活性和药效学标志物的开发
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2010-12-29 , DOI: 10.1158/1535-7163.mct-10-0760
Timothy A Yap ₁ , Mike I Walton , Lisa-Jane K Hunter , Melanie Valenti , Alexis de Haven Brandon , Paul D Eve , Ruth Ruddle , Simon P Heaton , Alan Henley , Lisa Pickard , Gowri Vijayaraghavan , John J Caldwell , Neil T Thompson , Wynne Aherne , Florence I Raynaud , Suzanne A Eccles , Paul Workman , Ian Collins , Michelle D Garrett

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AKT 在癌症中经常被解除管制，使其成为有吸引力的抗癌药物靶点。CCT128930 是一种使用基于片段和结构的方法发现的新型 ATP 竞争性 AKT 抑制剂。它是一种有效的、先进的先导吡咯并嘧啶化合物，通过靶向单个氨基酸差异实现对 AKT 的选择性，而不是 PKA。CCT128930 表现出显着的抗增殖活性，并在体外多种肿瘤细胞系中抑制了一系列 AKT 底物的磷酸化，这与 AKT 抑制一致。CCT128930 在 PTEN 缺失的 U87MG 人胶质母细胞瘤细胞中引起 G1 期阻滞，与 AKT 通路阻断一致。药代动力学研究表明，在人类肿瘤异种移植物中可以达到 CCT128930 的潜在活性浓度。此外，CCT128930 还阻断了 U87MG 肿瘤异种移植物中几种下游 AKT 生物标志物的磷酸化，表明体内 AKT 抑制。在 U87MG 和 HER2 阳性、PIK3CA 突变 BT474 人乳腺癌异种移植物中观察到 CCT128930 的抗肿瘤活性，与其药代动力学和药效学特性一致。提出了一种定量免疫荧光测定法，用于测量毛囊中 AKT 底物 PRAS40 的磷酸化和总蛋白表达。pThr246 PRAS40 在体内 CCT128930 处理的小鼠胡须毛囊和体外处理的人类毛囊中发生显着降低，总 PRAS40 变化很小。总之，CCT128930 是一种新型、选择性和有效的 AKT 抑制剂，可在体外和体内阻断 AKT 活性并诱导显着的抗肿瘤反应。我们还开发了一种新的生物标志物检测方法，用于抑制人毛囊中的 AKT，目前正在临床试验中使用。摩尔癌症治疗; 10(2); 360-71。©2010 AACR。

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Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials. Mol Cancer Ther; 10(2); 360–71. ©2010 AACR.

更新日期：2010-12-29

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