Development of sulfonamide AKT PH domain inhibitors

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 examin...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-03, Vol.19 (6), p.2046-2054
Main Authors: Ahad, Ali Md, Zuohe, Song, Du-Cuny, Lei, Moses, Sylvestor A., Zhou, Li Li, Zhang, Shuxing, Powis, Garth, Meuillet, Emmanuelle J., Mash, Eugene A.
Format: Article
Language:English
Subjects:
AKT
Anticancer
Antineoplastic agents
apoptosis
Binding Sites
Biological and medical sciences
Cell Line, Tumor
Computer Simulation
Drug design
Drug development
General aspects
Humans
Medical sciences
PH domain
Pharmacology. Drug treatments
pleckstrin
Protein Binding
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
signal transduction
Structure-Activity Relationship
structure-activity relationships
sulfonamides
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.01.049