Development of sulfonamide AKT PH domain inhibitors

Ali Md Ahad, Song Zuohe, Lei Du-Cuny, Sylvestor A. Moses, Li Li Zhou, Shuxing Zhang, Garth Powis, Emmanuelle J. Meuillet, Eugene A. Mash

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2046-2054
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number6
DOIs
StatePublished - Mar 15 2011

Keywords

  • AKT
  • Anticancer
  • Drug design
  • Drug development
  • PH domain

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Ahad, A. M., Zuohe, S., Du-Cuny, L., Moses, S. A., Zhou, L. L., Zhang, S., Powis, G., Meuillet, E. J., & Mash, E. A. (2011). Development of sulfonamide AKT PH domain inhibitors. Bioorganic and Medicinal Chemistry, 19(6), 2046-2054. https://doi.org/10.1016/j.bmc.2011.01.049