57671-28-0Relevant articles and documents
IRAK DEGRADERS AND USES THEREOF
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Paragraph 2050; 2051, (2019/07/10)
The present invention provides compounds, compositions thereof, and methods of using the same.
SMALL MOLECULES
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Page/Page column 16; 17; 39; 40, (2018/11/10)
Compounds having the general structure A - L - B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1 B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.
Homo-PROTACs: Bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Maniaci, Chiara,Hughes, Scott J.,Testa, Andrea,Chen, Wenzhang,Lamont, Douglas J.,Rocha, Sonia,Alessi, Dario R.,Romeo, Roberto,Ciulli, Alessio
, (2017/10/16)
E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.
ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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Paragraph 00391, (2017/02/09)
The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
Design and synthesis of novel hydrophilic spacers for the reduction of nonspecific binding proteins on affinity resins
Shiyama, Takaaki,Furuya, Minoru,Yamazaki, Akira,Terada, Tomohiro,Tanaka, Akito
, p. 2831 - 2841 (2007/10/03)
Tubulin and actin often bind nonspecifically to affinity chromatography resins, complicating research toward identifying the cellular targets. Reduction of nonspecific binding proteins is important for success in finding such targets. We herein disclose the design, synthesis, and effectiveness in reduction of nonspecific binding proteins, of novel hydrophilic spacers (2-5), which were introduced between matrices and a ligand. Among them, tartaric acid derivative (5) exhibited the most effective reduction of nonspecific binding proteins, whilst maintaining binding of the target protein. Introduction of 5 on TOYOPEARL reduced tubulin and actin by almost 65% and 90% compared to that without the hydrophilic spacer, respectively, with effective binding to the target protein, FKBP12.
Synthesis and analysis of polyethylene glycol linked P-glycoprotein-specific homodimers based on (-)-stipiamide
Andrus, Merritt B.,Turner, Timothy M.,Updegraff, Emily P.,Sauna, Zuben E.,Ambudkar, Suresh V.
, p. 3819 - 3822 (2007/10/03)
A series of five homodimeric polyethylene glycol (PEG) linked homodimers based on the multidrug resistance reversal agent (-)-stipiamide were made and tested for their ability to interact with P-glycoprotein, the protein responsible for multidrug resistance, using ATPase and photoaffinity displacement assays. Key reactions include a new alkoxide-mesylate displacement for the assembly of the PEG linkers and a double Sonogashira coupling reaction.
A convenient synthetic route to differentially functionalized long chain polyethylene glycols
Burns,Field,Hashimoto,Petteys,Ridley,Samankumara Sandanayake
, p. 2337 - 2347 (2007/10/03)
A convenient and efficient synthetic route to differentially functionalized polyethylene glycols (PEGs) starting from cheap commercially available materials is reported. Selectively protected triethylene glycol or tetraethylene glycol have been reacted with a second PEG bearing both a protecting group and a leaving group.
A novel way for hydroxyethylation by using clay catalysts
Sallay, Peter,Bekassy, Sandor,Ahmed, Mohamed H.,Farkas, Laszlo,Rusznak, Istvan
, p. 661 - 664 (2007/10/03)
Hydroxyethylation of aralkyl alcohols (benzyl alcohol, 2-phenylethanol, 3-phenylpropanol) in the presence of a clay catalyst (K10) was successful. This method has some advantages in contrast with the conventional ones: effective, works at mild reaction conditions, ease the separation of catalyst from the reaction mixture.
Lack of effect of the length of oligoglycine- and oligo(ethylene glycol)-derived para-substituents on the affinity of benzenesulfonamides for carbonic anhydrase II in solution
Jain, Ahamindra,Huang, Shaw G.,Whitesides, George M.
, p. 5057 - 5062 (2007/10/02)
Using 1H NMR spectroscopy, values of T2 have been determined for the methylene protons of the oligoglycine moieties of para-substituted benzenesulfonamides having structures H2NO2SC6H4CO(Gly)(n)OH (n = 1-6) bound at the active site of bovine carbonic anhydrase II (CA, EC 4.2.1.1). These values have been correlated with measurements of dissociation constants of these complexes, in order to infer motion of these ligands when bound to the enzyme. Motion of glycines 1-3 (those closest to the aryl ring) is hindered by their proximity to the protein; motion of glycines 4-6 is relatively unhindered. Despite the restriction to motion inferred for glycines 1-3, the values of K(d) for the six compounds (n = 1-6, 1-6) are indistinguishable within experimental uncertainty (± 20%): K(d) in μM (n) 0.30 (1); 0.26 (2); 0.33 (3); 0.37 (4); 0.37 (5); 0.34 (6). There is, therefore, an unexpected compensation of the loss in conformational entropy on binding by another contributor to the free energy.
