Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome.

Both enantiomers of 1‐naphthylglycine were obtained in 99% ee by enzymatic resolution of the corresponding racemic amino acid amide, giving access to the novel ligands (R)‐ and (S)‐naphthylbis(oxazoline). Initial studies provided insight into the scope and limitations of the (S)‐naphthyl‐substituted bis(oxazoline) and its steric influence compared to other bis(oxazolines) in catalytic asymmetric synthesis. (© Wiley‐VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)

p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors; however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achieving potency and selectivity through targeting an inactive state of the kinases induced by a unique folded P-loop conformation. Using a rapid, systematic combinatorial synthetic approach, we identified compound 93 (SR-318) with excellent potency and selectivity for p38α/β, which potently inhibited the TNF-α release in whole blood. SR-318 therefore presents a potent and selective type-II inhibitor of p38α/β that can be used as a chemical probe for targeting this particular inactive state of these two p38 isoforms.

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Novel, efficient synthetic pathways to DAH, KDO, and 2-deoxy-beta-KDO are described. Ring-closing metathesis (RCM) of highly functionalized alpha-alkoxyacrylate fragments resulted in a series of synthetically versatile oxygen heterocyclic intermediates. Further functionalization of the resulting enol ether double bond and subsequent deprotection provided the natural products in high overall yields, starting from commercially available protected sugars.