Development of sulfonamide AKT PH domain inhibitors.

Ahad, A.M., Zuohe, S., Du-Cuny, L., Moses, S.A., Zhou, L.L., Zhang, S., Powis, G., Meuillet, E.J., Mash, E.A.

Journal	Bioorg Med Chem Lett	Year	2011
Species	Human	Volume	19
Analytes Measured	Akt	Page #	2046-54
Matrix Tested	BxPC-3 pancreatic cancer cell lysates	Category	Phosphoproteins & Intracellular Markers

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.