Our cells function in the continuous mode of producing and degrading proteins, keeping the balance between these two processes to maintain a healthy cellular function. However, sometimes the produced proteins might be defective, accumulating and causing pathological effects. This is one of the examples when hijacking the naturally occurring process of protein degradation becomes highly useful for rescuing the cells.
When the time comes, in the majority of cases ubiquitin-proteasome system (UPS) takes over proteins. The sequence of enzymatic reactions leads to marking doomed proteins by the ubiquitin chain, which is done by E3 ubiquitin ligase. This causes the signaling cascade and, consequently, proteasomal recycling of proteins into the new building blocks.
Scientists figured out a way to force E3 ubiquitin ligase to get in proximity with any protein of interest so that the UPS can be involved in the targeted protein degradation -- by applying "molecular glues" or proteolysis-targeting chimeras, or PROTACs, the two most popular strategies to go about protein degradation.
Molecular glues and PROTACs -- what, why, and how?
Molecular glues are small molecules that stick two proteins together: typically a pathological protein and E3 ubiquitin ligase. With this reaction, molecular glues induce the poly-ubiquitinylation of “unwanted” proteins, which otherwise wouldn’t happen or would have a significantly slower rate. Nonetheless, a simple concept challenges the drug design process: the small molecule should bind one protein and modify its 3D structure so that it can bind the other protein of interest. A not-straightforward process makes the molecule’s structure prediction process more vague and complex.
Another approach in targeted protein degradation -- proteolysis-targeting chimeras, or PROTACs -- might resolve some of the molecular glue design challenges but simultaneously bring new ones. In brief, while molecular glue is a single molecule that embodies all the functions in one module, PROTACs are bifunctional molecules. This means they have separate domains binding E3 ligase and POI, joined by a linker in between, altogether resembling a dumbbell-shaped object. In recent years PROTACs discovery went through accelerated growth, with multiple companies signing new collaborations and adding protein degraders to their pipeline profiles.
Even though PROTACs are promising, they have several significant limitations. First of all, the POI should have a druggable pocket to bind the chimera’s domain, but only a subset of proteins is considered druggable. Additionally, a bigger size of PROTACs might lead to bioavailability challenges. Potentially, molecular glues might help to overcome these limitations.
The molecular glues industry is heating up
Recently molecular glues started attracting more attention from multiple investors and induced deals between big pharma companies and biotech start-ups. In October 2022, it was announced that Bristol Myers Squibb partnered up with San Francisco-based biotech SyntheX to develop targeted protein degraders therapeutics. The collaboration will be focused explicitly on discovering molecular glue degraders. Under the terms of the agreement, SyntheX will receive a combined upfront payment and up to $550 million in performance-based milestone payments.
SyntheX has developed proprietary platforms that leverage the power of synthetic biology to build next-generation drug discovery engines. This allows the company to discover functional molecular glues using a pre-specified E3 ligase and a POI.
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