“…There is a significant overexpression of mRNA for ErbB-2 in many breast cancers, with an associated increase in the levels of its phosphorylated gene product, p185erbB-2. Inhibitors of Grb2 SH2 domain binding could potentially uncouple p185erbB-2 from the Ras pathway and, in so doing, attenuate its transforming effects. , The possible therapeutic utility of Grb2 SH2 domain inhibitors has made their development an important area of research. ,− 1 …”
Section: Introductionmentioning
confidence: 99%
“…5,6 The possible therapeutic utility of Grb2 SH2 domain inhibitors has made their development an important area of research. 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Although pTyr residues play central roles in ligand recognition and binding by SH2 domains, their hydrolytic lability to cellular phosphatases limits their utility for inhibitor design. For this reason, pTyr mimetics have become important tools for developing SH2 domain antagonists, with a particular emphasis on phosphate surrogates having been dictated by the essential role of the phosphate group in pTyr binding affinity.…”
Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N(alpha)()-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.
“…There is a significant overexpression of mRNA for ErbB-2 in many breast cancers, with an associated increase in the levels of its phosphorylated gene product, p185erbB-2. Inhibitors of Grb2 SH2 domain binding could potentially uncouple p185erbB-2 from the Ras pathway and, in so doing, attenuate its transforming effects. , The possible therapeutic utility of Grb2 SH2 domain inhibitors has made their development an important area of research. ,− 1 …”
Section: Introductionmentioning
confidence: 99%
“…5,6 The possible therapeutic utility of Grb2 SH2 domain inhibitors has made their development an important area of research. 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Although pTyr residues play central roles in ligand recognition and binding by SH2 domains, their hydrolytic lability to cellular phosphatases limits their utility for inhibitor design. For this reason, pTyr mimetics have become important tools for developing SH2 domain antagonists, with a particular emphasis on phosphate surrogates having been dictated by the essential role of the phosphate group in pTyr binding affinity.…”
Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N(alpha)()-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.
“…Therefore, development of Grb2 SH2 domain binding blockers has important implications for treatment of a variety of diseases, including several cancers . Recently, we found that actinomycins, well-known DNA intercalators, inhibited the Grb2−Shc binding in in vitro and cell-based assays. , …”
A new secondary metabolite, 8-O-methylsclerotiorinamine (1), was isolated from a strain of Penicillium multicolor, and its structure was established using NMR spectroscopy and chemical evidence. The metabolite inhibited significantly the binding between the Grb2-SH2 domain and the phosphopeptide derived from the Shc protein and also blocked the protein-protein interactions of Grb2-Shc in cell-based experiments, with IC(50) values of 5.3 and 50 microM, respectively.
“…Azaphilones are renowned for a wide range of pharmaceutical applications as a cytotoxic, anti-inflammatory, anti-viral, antioxidant, and antimicrobial agents (Osmanova et al 2010). In addition to its antibacterial, antifungal (Chidananda et al 2006;Lucas et al 2007), and anti-cancer activities (Giridharan et al 2012), sclerotiorin also acts as an endothelin receptor binding molecule (Pairet et al 1995), as well as it inhibits Grb-2-Sch interaction (Nam et al 1998), gp120-CD4 binding (Matsuzaki et al 1995), cholesteryl ester transfer protein (Barter and Rye 1994), and the activity of lipase (Lucas et al 2007), aldose reductase (Kador 1988), soybean lipoxygenase (LOX-I) (Chidananda and Sattur 2007), and monamine oxidase (Fujimoto 1990).…”
Purpose
Sclerotiorin, an azaphilone produced by some filamentous fungi including Penicillium sclerotiorum, is a pigment with variety of biological activities including lipoxygenase inhibition, reduction of cholesterol levels, and anti-cancer properties. Sclerotiorin has potential use in pharmaceutical as well as food industries. In this context, the purpose of this study was to provide a simple and robust procedure for optimised production of sclerotiorin by P. sclerotiorum using a central composite design developed through response surface methodology (RSM) and to identify the molecule(s) involved in the signalling mechanism in P. sclerotiorum.
Methods
The optimisation of sclerotiorin production was carried out using RSM in shaken flasks and the obtained results were then replicated using a 2-L stirred tank bioreactor. Penicillium sclerotiorum ethyl acetate culture extract was analysed using thin layer chromatography (TLC) and potential signalling molecules were identified using Gas chromatography-mass spectrometry (GC-MS).
Results
The experimental studies suggested an increase in the sclerotiorin production by 2.1-fold and 2.2-fold in shaken flasks and stirred tank bioreactors respectively. Further analysis of P. sclerotiorum ethyl acetate culture extract reported the presence of ricinoleic acid, an oxylipin, belonging to a family of signalling molecules tentatively involved in the enhancement of sclerotiorin production.
Conclusion
This paper has highlighted the positive effect of the optimal supplementation of P. sclerotiorum culture extracts for enhanced production of sclerotiorin. It has also examined potential molecules involved in the signalling mechanism in P. sclerotiorum culture extract for the overproduction of sclerotiorin.
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