Targeted Protein Degradation as an Approach to Treatment
Targeted protein degradation is a term that covers a range of possible approaches to more selectively removing specific modified proteins from cells than has traditionally been possible. Researchers here provide an example of this type of work, targeting a modification of p38 in the context of Alzheimer's disease. This is a good illustration of the capabilities of this class of therapy, but probably not the best illustration of a good target: this still seems like a matter of messing with metabolism made dysfunctional by damage rather than targeting the underlying damage itself for repair.
Recent progress in the field of targeted protein degradation (TPD) has proven its immense potential as a novel therapeutic modality in drug discovery. In 2015, researchers devised a phthalimide-based small molecule that promotes degradation of transcriptional coactivator BRD4 by hijacking the Cereblon (CRBN) E3 ubiquitin ligase complex. In the same year, others also reported a TPD technology recruiting the von Hippel-Lindau (VHL) E3 ligase complex, commonly referred to as proteolysis-targeting chimeras (PROTACs). These technologies feature bifunctional small molecules that bring the proteins of interest into proximity with the E3 ubiquitin ligase complexes for ubiquitination and subsequent proteasomal degradation.
Such TPD-based small molecules have several advantages over traditional small molecule inhibitors in that they eliminate the target protein instead of modulating its function. TPD technology thus can complement nucleic acid-based gene knockdown in removing unwanted intracellular proteins. In addition, the TPD technique can target a plethora of proteins in various compartments of the cell, including disease-causing proteins that have previously been considered undruggable with the conventional small-molecule approach. Recently, several strategies have been suggested to potentiate therapeutic efficacy of TPD technology. In particular, TPD molecules that recognize and bind to the protein with specific post-translational modifications (PTMs), such as phosphorylation, may be a novel strategy to induce selective degradation of pathological proteins attributed to aberrant PTMs. However, a TPD molecule specifically targeting post-translationally modified proteins has not been reported yet.
It has been reported that phosphorylated p38 (p-p38) is significantly upregulated under pathological conditions, such as chronic inflammation, thus triggering downstream signal transduction and leading to pathological deterioration. P38 dysfunction has been implicated in a variety of medical disorders, such as neuroinflammation, ischemia, and cognitive impairment. Our previous study showed that enzymatic inhibition of p38 alleviated pathological symptoms of Alzheimer′s disease (AD), particularly neuroinflammation and accumulation of beta-amyloid (Aβ) and tau proteins. The therapeutic potential of inhibiting p38 in neurodegeneration has been investigated in several clinical trials, but there has been no success yet partly due to off-target effects and insufficient efficacy.
In this study, we use targeted protein degradation as a strategy to induce selective degradation of p-p38. Based on the phosphorylation-dependent conformational difference in p38, we rationally designed and synthesized a series of p-p38-degrading small molecules, consisting of a p-p38 ligand and pomalidomide that can recruit the CRBN E3 ubiquitin ligase complex. We found that one candidate molecule induced selective in vivo degradation of p-p38 and ameliorated neurodegenerative symptoms including neuroinflammation, Aβ deposition, and memory loss. Overall, this study highlights selective targeting of p38 bearing a specific PTM for proteasomal degradation, providing a novel therapeutic approach for the treatment of AD.