Molecular Glue And Its Application In New Drug Development

WATERTOWN, Mass. - June 28, 2022 - PRLog -- 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.

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.

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