227312-86-9Relevant academic research and scientific papers
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 D.
supporting information; experimental part, p. 1764 - 1771 (2009/09/05)
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.
SUBSTRATE-MIMETIC AKT INHIBITOR
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Page/Page column 4-5; 10-11; 3/14; 9/14, (2008/12/06)
Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with 0 a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionallv homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterpartsand are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Modifications of the GSK3β substrate sequence to produce substrate-mimetic inhibitors of Akt as potential anti-cancer therapeutics
Kayser, Katherine J.,Glenn, Matthew P.,Sebti, Said M.,Cheng, Jin Q.,Hamilton, Andrew D.
, p. 2068 - 2073 (2007/10/03)
Amplification, overexpression, and elevated activation of Akt have been detected in many human malignancies making it an important target for cancer therapy. The Akt substrate-binding site offers a large number of potential interactions to an appropriatel
Synthesis and structure-activity study of protease inhibitors. V. Chemical modification of 6-amidino-2-naphthyl 4-guanidinobenzoate
Nakayama,Taira,Ikeda,Ashizawa,Oda,Arakawa,Fujii
, p. 117 - 125 (2007/10/02)
By developing 6-amidino-2-naphthyl 4-guanidinobenzoate (I, FUT-175) as a basic structure, its various derivatives were synthesized and their inhibitory activities on trypsin, plasmin, kallikrein, thrombin, C1r and C1s as well as on complement-mediated hemolysis were examined. The protective effect of these compounds on complement-mediated Forssman shock was also examined in guinea pigs. 6-Amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate (41, FUT-187) was found to be a suitable compound for oral administration with anti-complement activity superior to that of compound I.
