In recent years, targeted protein degraders have entered the mainstream of drug development at a very rapid rate. Thalidomide and its derivatives for the treatment of multiple myeloma and other conditions have demonstrated the potential of protein degraders, while ARV-471, an estrogen receptor degrader based on the drug development of thalidomide, is targeted at the early stage of breast cancer has continued to show superior performance in clinical trials.

Currently, targeted protein degradators are mainly divided into two types: small molecular "molecular glue" and biffunctional molecular degradators (PROTAC), both of which can mediate the binding and degradation of E3 ubiquitin ligase to the target protein. But the definition of the former has always been so vague that people often lump them together. In fact, there are significant differences in the mechanism of action and thermodynamic behavior between the two. The most important difference is that the "molecular glue" can act on non-drug targets without small molecule binding pockets. Accurately understanding and exploiting these differences will provide new ideas for the development of targeted drugs and have the potential to revolutionize the pharmaceutical industry.

Ning Zheng and his team from the University of Washington first proposed the concept of "molecular glue" in 2007 based on the structure of auxin sensory complex in plants. The core of this paper is to make a rigorous definition of "molecular glue" to clarify the difference between PROTAC and "molecular glue", and provide theoretical guidance for drug creation of "molecular glue". Zheng ning's team conducted a comparative study on the topological structure and thermodynamic characteristics of a variety of classic "molecular glue" systems, such as double nano antibody cannabidiol sensor, plant auxin sensing complex, and cancer drugs Lenalidomide and Pomalidomide. Distilled out two key properties common to the "molecular glue".

Therefore, the in-depth study of "molecular glue" may break a new road in the research and development of new drugs. Although PROTAC also works through protein degradation, its design begins with a binding chemical group to a target protein. Therefore, PROTAC cannot act on non-generic target proteins without pockets, and its application is naturally different from that of "molecular glue".

First, the "molecular glue" has no affinity for the target protein. But the "molecular glue" binds to E3 ubiquitin ligase and, with its help, makes contact with the target protein, thereby mediating and enhancing the interaction between the target protein and E3 ubiquitin ligase. This property allows the "molecular glue" to down-regulate non-viable targets that do not have small molecule binding pockets by means of protein degradation.

It is worth noting that most proteins in human cells do not have small molecule binding pockets, including many important cancer-related proteins (such as c-Myc) and the disordered protein Tau closely related to neurodegenerative diseases. Therefore, in-depth research on "molecular glue" may break a new path in the development of new drugs. Although PROTAC also acts through protein degradation, its design begins with a chemical moiety that binds to the target protein. Therefore, PROTAC cannot act on non-drugable target proteins without pockets, and its application is naturally different from "molecular glue".

Second, in the absence of a "molecular glue", the target protein needs to have a nonfunctional but detectable weak affinity for the E3 ubiquitin ligase. By filling the voids at the interface where they interact, the "molecular glue" further enlarges the binding interface of the two and elevates it to a functionally strong interaction. Notably, the inherently weak interaction of the target protein with the E3 ubiquitin ligase is extremely surprising. It has long been misunderstood in the field that "molecular glue" can bind two proteins with absolutely no affinity, thus blurring or even misleading the route of "molecular glue" drug creation. This study provides valuable guidance on how to select a potential E3 ubiquitin ligase for a well-defined target protein, which is a critical first step in the prospective development of "molecular glue" small-molecule degraders.

In addition, the optimization process of Hit-to-Lead in the development of "molecular glue" is very critical. But the ternary interactions mediated by "molecular glue" are far more complex than the binary interactions between inhibitor drugs and target proteins.

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