57671-28-0Relevant articles and documents
IRAK DEGRADERS AND USES THEREOF
-
Paragraph 2050; 2051, (2019/07/10)
The present invention provides compounds, compositions thereof, and methods of using the same.
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.
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.
