Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents

Katherine J. Kayser-Bricker, Matthew P. Glenn, Sang Hoon Lee, Said M. Sebti, Jin Q. Cheng, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3β substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a-b, which have affinities of 17 and 12 μM, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design.

Original languageEnglish (US)
Pages (from-to)1764-1771
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2009

Fingerprint

Substrates
Peptidomimetics
Molecular Probes
Neoplasms
Drug Design
Substrate Specificity
Cell Survival
Carcinogenesis
Adenosine Triphosphate
Chemotherapy
Apoptosis
Amino Acids
Drug Therapy
Cells
Molecules
Pharmaceutical Preparations
Therapeutics
Lead

Keywords

  • Akt
  • Cancer
  • Inhibitor
  • Protein kinase B
  • Substrate-mimetic

ASJC Scopus subject areas

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

Cite this

Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents. / Kayser-Bricker, Katherine J.; Glenn, Matthew P.; Lee, Sang Hoon; Sebti, Said M.; Cheng, Jin Q.; Hamilton, Andrew.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 4, 15.02.2009, p. 1764-1771.

Research output: Contribution to journalArticle

Kayser-Bricker, Katherine J. ; Glenn, Matthew P. ; Lee, Sang Hoon ; Sebti, Said M. ; Cheng, Jin Q. ; Hamilton, Andrew. / Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 4. pp. 1764-1771.
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