Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
J Med Chem. 2010 Mar 11;53(5):2239-49. doi: 10.1021/jm901788j.
Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.
蛋白激酶 B（PKB 或 Akt）是调节生长和存活的细胞内信号通路的重要组成部分。PKB 信号通路在癌症中经常失调，因此 PKB 的抑制剂具有作为抗肿瘤药物的潜力。通过对一系列 4-苄基-1-（7H-吡咯并[2,3-d]嘧啶-4-基）哌啶-4-胺的脂溶性取代进行优化，提供了 ATP 竞争性的、纳摩尔级的抑制剂，对 PKB 的抑制作用比密切相关的激酶 PKA 高 150 倍。尽管在细胞测定中有效，但含有 4-氨基-4-苄基哌啶的化合物在体内发生代谢，导致快速清除和低口服生物利用度。在哌啶和脂溶性取代基之间的连接基团的变化确定了 4-氨基-1-（7H-吡咯并[2,3-d]嘧啶-4-基）哌啶-4-甲酰胺作为强效和口服生物利用度的 PKB 抑制剂。代表性化合物在体内调节了 PKB 信号通路的生物标志物，并在可耐受剂量下强烈抑制裸鼠中人肿瘤异种移植物的生长。
