Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38 alpha

Cubillos-Rojas, M; Loren, G; Hakim, YZ; Verdaguer, X; Riera, A; Nebreda, AR

Abstract

Simple Summary
The compounds named PROTACs are formed by two fragments, which bring together a particular protein with a ubiquitinating enzyme. This allows ubiquitination and degradation of the targeted protein. Ubiquitination-mediated protein degradation is an important regulatory process to control the expression levels of proteins and maintain the homeostatic conditions in cells. Thus, by re-directing a mechanism that is normally used for cell regulation, PROTACs allow to remove specific proteins associated to particular diseases or pathological conditions. In this paper, we report a type of PROTAC that targets for degradation the protein named p38 alpha, whose functions have been linked to cancer and other diseases. We show that these PROTACs effectively reduce p38 alpha protein expression not only in several cancer cell lines but also in tumors generated in mice. These compounds may provide an attractive strategy to evaluate potential therapeutic applications for targeting p38 alpha in the clinical context.
We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38 alpha for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38 alpha. We provide evidence that these compounds can induce the specific degradation of p38 alpha, but not p38 beta and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38 alpha-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38 alpha degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38 alpha degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38 alpha signaling in cultured cells and in vivo.

Keywords: p38 MAPK; PROTAC; protein degradation; VHL

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