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 Meuillet, Eugene A Mash

Research output: Contribution to journalArticle

23 Citations (Scopus)

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

Fingerprint

Sulfonamides
Assays
Cells
Phosphatidylinositol 3-Kinase
Apoptosis
Lead compounds
Competitive Binding
Surface Plasmon Resonance
Surface plasmon resonance
Structure-Activity Relationship
platelet protein P47
Pleckstrin Homology Domains
Neoplasms
Lead

Keywords

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

ASJC Scopus subject areas

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

Cite this

Ahad, A. M., Zuohe, S., Du-Cuny, L., Moses, S. A., Zhou, L. L., Zhang, S., ... 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

Development of sulfonamide AKT PH domain inhibitors. / Ahad, Ali Md; Zuohe, Song; Du-Cuny, Lei; Moses, Sylvestor A.; Zhou, Li Li; Zhang, Shuxing; Powis, Garth; Meuillet, Emmanuelle; Mash, Eugene A.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 6, 15.03.2011, p. 2046-2054.

Research output: Contribution to journalArticle

Ahad, AM, Zuohe, S, Du-Cuny, L, Moses, SA, Zhou, LL, Zhang, S, Powis, G, Meuillet, E & Mash, EA 2011, 'Development of sulfonamide AKT PH domain inhibitors', Bioorganic and Medicinal Chemistry, vol. 19, no. 6, pp. 2046-2054. https://doi.org/10.1016/j.bmc.2011.01.049
Ahad AM, Zuohe S, Du-Cuny L, Moses SA, Zhou LL, Zhang S et al. Development of sulfonamide AKT PH domain inhibitors. Bioorganic and Medicinal Chemistry. 2011 Mar 15;19(6):2046-2054. https://doi.org/10.1016/j.bmc.2011.01.049
Ahad, Ali Md ; Zuohe, Song ; Du-Cuny, Lei ; Moses, Sylvestor A. ; Zhou, Li Li ; Zhang, Shuxing ; Powis, Garth ; Meuillet, Emmanuelle ; Mash, Eugene A. / Development of sulfonamide AKT PH domain inhibitors. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 6. pp. 2046-2054.
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