Leveraging ligand affinity and properties: discovery of novel benzamide-type cereblon binders for the design of PROTACs

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds

vuv synchrotron light as a technique for studying the interface quality and properties of thin overlayers

The measurements presented here show the value of synchrotron light for determining both the electronic structure of overlayers, and the physical nature of the overlayer-substrate interface. A comparison is given between deposited layers and thermally stabilized layers. Estimates are also made of the bonding energy between the overlayer and substrate

Cooperative configuration change in EuPd<SUB>2</SUB>Si<SUB>2</SUB>

4f7&#x21C4;4f6+e charge fluctuations (inferered from 151Eu Mossbauer spectroscopy) in EuPd2Si2 show a strong nonlinear thermal dependence when compared to those observed in dilute Eu in LaPd2Si2. This nonlinear behavior is well described by extending the interconfigurational fluctuation model to include a cooperative intersite coupling of the interconfigurational fluctuation excitation energy to the 4f occupation number. Eu nuclear vibrational damping occurs in the region of greatest charge instability