Cell-permeable inhibitors

Contradictory results were obtained from studies with berKamide analogs of anacardic acid. While CTPB 4 (Figure 11.2) was reported to be an activator of p300 [13], the related cyano-benzamides S and 6 (Figure 11.2) aded as cell-permeable inhibitors of p300, exhibiting a similar profile to anacardic acid [15]. 

Recently, a cell-permeable inhibitor of the human Gcn5 named MB-3 8 was discovered (Figure 11.3). This compound is structurally related to the a-methylene-y-butyrolactone class of compounds, a common structural element in a plethora of natural products. MB-3 was developed by appropriate derivatization of the basic y-butyrolactone motif without the arbitrary screening of large compound libraries. Interestingly, the length of the aliphatic side-chain is crucial for biological activity [17, 18]. 

M. S. Macauley, Y. He, T. M. Gloster, K. A. Stubbs, G. J. Davies, and D. J. Vocadlo, Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes, Chem. Biol., 1 (2010) 937-948. 

In contrast to enzyme assays, cell-based assays present the target in a more physiological milieu. With enzyme assays, it may be difficult to purify and express active kinases and phosphatases in their full-length forms and they may require the use of fusion proteins with kinase activity domains. Cell-based technologies, on the other hand, present the opportunity to express the targets with regulatory domains included. Furthermore, cell-based assays usually detect only cell-permeable inhibitors and have the potential to identify more unusual mechanisms, as described earlier. 

Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirch- 62. hausen T. Dynasore, a cell-permeable inhibitor of dynamin. Dev. 

Cell-permeable inhibitor of Ras interaction with c-Raf-1 and activation of ERK. 

Cell-permeable inhibitors of PI3K family lipid kinases. 

Of course, cell permeability is not always a prerequisite for biologic activity. In one example, Vaghefi et al. (24) proposed that selective phosphonate inhibitors of galactosyltransferase might exhibit activity at the surface of the tumor cell membranes in such cases, a cell permeable inhibitor would be unnecessary. Although no in vivo testing was conducted, phosphonate... 

In order to improve cellular permeabihty nonpeptidic pTyr mimetics have been designed and compound 179 was found as a potent, cell permeable inhibitor of PTPIB [57]. 

Lee JH, Zhang Q, Jo S et al (2011) Novel pyrrolopyrimidine-based a-helix mimetics cell-permeable inhibitors of protein-protein interactions. J Am Chem Soc 133 676-679... 

The cell-permeable inhibitors induce dramatic changes in cell morphology. These have been documented in several cell types (see Hirano etal., 1992). In 3T3 fibroblasts the changes involve a reorganization of F-actin and its gradual aggregation into a ball-like structure that is connected to the nucleus via cables of intermediate filaments. Several proteins are phosphorylated, but of the major cytoskeletal proteins only vimentin and myosin were identified (Chartier et al., 1991 Hirano and Hartshorne, 1993). It is not known if these extensive changes occur in smooth muscle cells. 

In conjunction with our overview of glycomimetics that block protein-carbohydrate interactions, we also discuss strategies to develop inhibitors of carbohydrate-processing enzymes this section focuses on the enzymes involved in bacterial cell wall biosynthesis because it is an area in which many new advances have been made. Enzymes that utilize sugars and synthesize glycoconjugates unique to pathogens have been identified, and cell-permeable inhibitors can be used to explore their biological roles or validate a potential... 

Small molecule Smac mimetics Cell-permeable inhibitors of XIAP, cIAP-1, cIAP-2 Potentiate apoptosis in combination with TRIAL and TNF Preclinical 137... 

G. A., Kessler, B.M., Overkleeft, H.S., and Kisselev, A.F. (2007) A cell-permeable inhibitor and activity-based probe for the caspase-like activity of the proteasome. Bioorg. Med. Chem. Lett, 17, 3402-3405. 

Fusion of cyclic peptides with a cyclic cell-penetrating peptide has been realised to produce a potent selective, proteolytically stable, and biologically active bicyclic cell-permeable inhibitor (148) against peptidyl-prolyl cis-trans isomerase (Pinl). ... 

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