基于合成与结构的新型Akt抑制剂优化
Synthesis and structure based optimization of novel Akt inhibitors.
作者信息
Lippa Blaise, Pan Gonghua, Corbett Matthew, Li Chao, Kauffman Goss S, Pandit Jayvardhan, Robinson Shaughnessy, Wei Liuqing, Kozina Ekaterina, Marr Eric S, Borzillo Gary, Knauth Elisabeth, Barbacci-Tobin Elsa G, Vincent Patrick, Troutman Merin, Baker Deborah, Rajamohan Francis, Kakar Shefali, Clark Tracey, Morris Joel
机构信息
Pfizer, Inc., PGRD Groton, 558 Eastern Point Road, Groton, CT 06340, USA.
出版信息
Bioorg Med Chem Lett. 2008 Jun 1;18(11):3359-63. doi: 10.1016/j.bmcl.2008.04.034. Epub 2008 Apr 15.
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
基于高通量筛选得到的活性化合物，对Akt激酶的吡咯并嘧啶抑制剂进行了探索。两个先导系列的X射线共晶体结构有助于理解关键的结合相互作用、设计新的先导系列并提高活性。描述了这些系列的合成及其生物活性。发现螺吲哚啉13j对Akt1激酶的IC(50)为2.4±0.6 nM，对Akt细胞的活性为50±19 nM，在小鼠异种移植模型中对肿瘤生长的抑制率为68%（50 mg/kg，每日一次，口服）。
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