title: Development of sulfonamide AKT PH domain inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721-0041, USA.
authors.forename: Ali Md
authors.initials: AM
authors.lastname: Ahad
authors.forename: Song
authors.initials: S
authors.lastname: Zuohe
authors.forename: Lei
authors.initials: L
authors.lastname: Du-Cuny
authors.forename: Sylvestor A
authors.initials: SA
authors.lastname: Moses
authors.forename: Li Li
authors.initials: LL
authors.lastname: Zhou
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt