ABSTRACT
Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.
Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Proteolysis , Peptide Hydrolases/metabolism , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
Outflowing winds of multiphase plasma have been proposed to regulate the buildup of galaxies, but key aspects of these outflows have not been probed with observations. By using ultraviolet absorption spectroscopy, we show that "warm-hot" plasma at 10(5.5) kelvin contains 10 to 150 times more mass than the cold gas in a post-starburst galaxy wind. This wind extends to distances > 68 kiloparsecs, and at least some portion of it will escape. Moreover, the kinematical correlation of the cold and warm-hot phases indicates that the warm-hot plasma is related to the interaction of the cold matter with a hotter (unseen) phase at >>10(6) kelvin. Such multiphase winds can remove substantial masses and alter the evolution of post-starburst galaxies.
