PROTAC "changes" molecular glue: MDM2 degradation agent can actually degrade p53

Source: Medical Rubik's Cube Pro

The full name of PROTACs is Proteolysis-Targeting Chimeras, or proteolysis-targeting chimeras.

In recent years, as a new way to regulate protein homeostasis, PROTAC has received extensive attention from academia and industry.

CRBN is a part of CRL4 E3 ubiquitin ligase, which acts as a substrate receptor (SRs) to recognize substrate proteins and initiate the degradation process.

Simply put, molecular glue degradation agents are small molecules that can induce a new type of interaction between the E3 ubiquitin ligase substrate receptor (such as CRBN) and the target protein, resulting in the degradation of the target protein.

On April 4, a team of scientists from the University of Wisconsin-Madison published a paper published in the European Journal of Medicinal Chemistry and announced a new type of MDM2 degradant they had developed [1].

MDM2, the full name of mouse double minute 2 (mouse double minute 2), is a key negative regulator of p53 (a powerful tumor suppressor, the most frequently mutated gene in human cancer).

In August 2019, the team of scientists reported that they had developed a highly efficient MDM2-PROTAC-WB156[2].

Design of MDM2 degradation agent.

In order to overcome this bottleneck, scientists envisioned that fusion of different MDM2 ligands might enable MDM2 degradants to work in a wider range of cancers.

Surprisingly, the mechanism study showed that this new type of WB214 degrader did not activate p53.

Scientists conducted a series of experiments to investigate the underlying mechanism behind this effect.

Since the formation of ternary complexes is the prerequisite for proteasome degradation, the researchers further analyzed the situation of WB214 inducing the formation of ternary complexes and confirmed that WB214 can effectively induce the formation of ternary complexes in a dose-dependent manner.

Then, the study revealed that WB214 can still inhibit the growth of leukemia cells after degrading p53 because this degrading agent can also effectively degrade GSPT1.

Therefore, in this study, scientists at the University of Wisconsin-Madison also tested whether WB214 also degraded GSPT1.

Degradation characteristics of leukemia cells (Western blot analysis).

Finally, the scientists tried to develop a selective degrading agent for MDM2 or GSPT1.

In the discussion part of the paper, the authors pointed out that a very important lesson that this work has brought them is that when developing protein degradants, proteins (such as p53) that bind to target proteins (such as MDM2) may also act as " Bystanders" are degraded.
Most of the new substrates reported so far are CRBN, and as the E3 ubiquitin ligase family used to develop protein degrading agents becomes stronger, off-target effects may occur more.

Reference materials:

[1] BoWang et al.
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries.
European Journal of Medicinal Chemistry(2021).

[2] BoWang et al.
Development of selective small molecule MDM2 degraders based on nutlin.
European Journal of Medicinal Chemistry(2019).