How to design targeted protein degradation agents more effectively?

Targeted protein degradation agents represented by PROTACs are one of the hotspots in the development of new drugs

One end of the PROTAC molecule can bind to the target protein, and the other end can recruit E3 ubiquitin ligase to tag the target protein with ubiquitin to promote their degradation by the proteasome

BCL-xL and BCL-2 are members of the anti-apoptotic BCL-2 protein family, which play an important role in promoting tumorigenesis, progression, and drug resistance

The research team found that in the process of protein modification by ubiquitin, E3 ligase recruits E2 ligase and finally binds ubiquitin to lysine on the surface of the target protein

▲The process of protein modification by ubiquitin (picture source: Rogerdodd, CC BY-SA 3.

With the goal of improving the access of E2 ligase to lysine on the surface of the target protein, the researchers designed a series of innovative PROTAC molecules and discovered a PROTAC molecule that can simultaneously target and degrade BCL-xL and BCL-2

The researchers pointed out in the discussion section of the paper that whether the PROTAC molecule can successfully mediate the ubiquitin modification of the target protein not only needs to form a stable ternary structure with the E3 ligase and the target protein, but also whether there is a surface of the target protein that can be connected by E2 Enzyme access, the lysine linking the ubiquitin molecule is also crucial

Reference materials:

[1] Lv, et al.