Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721-0041, USA.
Bioorg Med Chem. 2011 Mar 15;19(6):2046-54. doi: 10.1016/j.bmc.2011.01.049. Epub 2011 Feb 1.
Disruption of the phosphatidylinositol 3-kinase/AKT signaling pathway can lead to apoptosis in cancer cells. Previously we identified a lead sulfonamide that selectively bound to the pleckstrin homology (PH) domain of AKT and induced apoptosis when present at low micromolar concentrations. To examine the effects of structural modification, a set of sulfonamides related to the lead compound was designed, synthesized, and tested for binding to the expressed PH domain of AKT using a surface plasmon resonance-based competitive binding assay. Cellular activity was determined by means of an assay for pAKT production and a cell killing assay using BxPC-3 cells. The most active compounds in the set are lipophilic and possess an aliphatic chain of the proper length. Results were interpreted with the aid of computational modeling. This paper represents the first structure-activity relationship (SAR) study of a large family of AKT PH domain inhibitors. Information obtained will be used in the design of the next generation of inhibitors of AKT PH domain function.
磷酸肌醇 3-激酶/AKT 信号通路的破坏可导致癌细胞凋亡。先前，我们鉴定出一种先导磺胺，它能选择性地与 AKT 的pleckstrin 同源（PH）结构域结合，并在低微摩尔浓度时诱导细胞凋亡。为了研究结构修饰的影响，设计、合成了一组与先导化合物相关的磺胺类化合物，并使用基于表面等离子体共振的竞争性结合测定法，检测它们与 AKT 表达 PH 结构域的结合情况。通过 pAKT 产生的测定法和使用 BxPC-3 细胞的细胞杀伤测定法来确定细胞活性。该组中最活跃的化合物具有亲脂性，并且具有适当长度的脂肪族链。借助于计算模型来解释结果。本文代表了 AKT PH 结构域抑制剂大家族的首次构效关系（SAR）研究。获得的信息将用于设计下一代 AKT PH 结构域功能抑制剂。
