What are the challenges and opportunities for the treatment of cancer protein degradation therapy?

Targeted protein degradation therapy is a hot area for new drug development.

The mechanism of protein degradation of medoamine drugs

The basic mechanism of action of protein degradation drugs is to use the ubiquitin-proteasome system (UPS) to induce the degradation of specific proteins.

▲Schematic diagram of the mechanism of action of protein degradation agents that regulate the binding characteristics of CRBN protein (picture source: Bristol-Myers Squibb official website)

Unique advantages of protein degradation mechanism

Compared with small molecule inhibitors that generally inhibit protease activity, the mechanism of protein degradation provides numerous advantages that are conducive to drug development.

Another advantage of a protein degradation agent is that it can be used to target some of the targets that are structural proteins that cause diseases.

▲Different mechanisms of action between protein degradation agents and traditional small molecule inhibitors (picture source: reference [2])

The mechanism of cancer resistance to protein degrading agents

Although most of the new generation of targeted protein degradation agents are still in the preclinical development stage, researchers have already observed the resistance of tumor cells to protein degradation agents.

From the experience of dosamine drugs, tumor cells can develop resistance to protein degrading agents through multiple pathways.

Another mechanism of resistance is to increase the level of other substrates of E3 ubiquitin ligase.

▲Multiple mechanisms of resistance to protein degradation (picture source: reference [1])

In addition to directly affecting the protein degradation mechanism, cancer cells can also avoid the effects of target protein degradation through mutations downstream of the signaling pathway.

Future opportunities for protein degradants

From a certain perspective, the success of dosamine drugs in the treatment of multiple myeloma and other blood cancers provides a clinical proof of concept for the development of a new generation of targeted protein degradation agents.

Innovative protein degradation mechanism

There are more than 600 types of E3 ubiquitin ligases in the human body, and the ubiquitin ligases currently used by most targeted protein degradation agents are still limited to a few such as CRBN or VHL.

Therefore, a big opportunity to expand the development of protein degradation agents is to expand the types of E3 ligases used, and even develop protein degradation methods that do not rely on specific E3 ubiquitin ligases.

▲By adding a lipophilic group (red) to the C24 bound to the EZH protein, the specific EZH protein degradation agent MS1843 is generated (picture source: reference [3])

Application of protein degradation agents in synthetic biology and cell therapy

In addition to directly producing anti-cancer activity, the structural unit based on protein degradation can be used as a molecular switch to regulate the function of cell therapy.

▲Using lenalidomide-sensing components to control the activity of CAR-T therapy (picture source: reference [1])

Conclusion

In the field of oncology, the development of targeted protein degradation therapies is at an exciting turning point.

Reference materials:

[1] Jan et al.

[2] Dhanusha A.

[3] Anqi Ma et al.