SJFδ, a 10-atom Linker PROTAC, Degrades p38δ

PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein. Therefore, this effect results in its targeted degradation. PROTACs couple a small molecule binder of a target protein to an E3 ubiquitin ligaserecruiting moiety via an intervening chemical linker. Especially, this hetero-bifunctional small molecule design induces the proximity between target protein and E3 ubiquitin ligase complex, which promotes the ubiquitination and subsequent degradation of the former.

The goal of PROTAC technology is to create a chimeric molecule that bridges any cancer-causing protein to an E3 ligase. In particular, PROTACs consist of one moiet, which is recognized by the E3 ligase. To date, efforts have largely focused on recruitment of the von Hippel-Lindau (VHL) and cereblon (CRBN) E3 ubiquitin ligases. This is because the discovery of high-affinity ligands for these two ligases. Fortunately, researchers generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau). As a result, based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ.

SJFδ a 10 atom Linker PROTAC Degrades p38δ 2019 06 11 - SJFδ, a 10-atom Linker PROTAC, Degrades p38δ

In this syudy, Blake E. Smith, et al discovered that the 10-atom linker PROTAC SJFδ. Moreover, they characterized the role of ternary complex formation in driving selectivity, showing that it is necessary for PROTAC-induced substrate ubiquitination. Besides, Blake E. Smith, et al also explored the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Gratifyingly, SJFδ degrades p38δwith strong capacity. SJFδ degrades p38δ with a DC50 of 46.17±9.85 nM and a Dmax of 99.41±3.31%.

Smith BE, et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 2019 Jan 10;10(1):131.