A trivalent PROTAC degrader with a 300-fold increase in degradation activity

A new technique for designing PROTAC molecules is described in an article published in the most recent issue of Nature Chemical Biology. SIM1, a trivalent molecule with three protein-binding domains, was found to bind target proteins more effectively, have longer-lasting and more efficient degradation, and have more effective anti-cancer activity.

PROTAC is a bifunctional molecule that binds to the target protein on one end and recruits E3 ubiquitin ligase on the other, causing ubiquitination and degradation of the target protein by the proteasome.

The Nobel Prize in Chemistry was awarded to Asron Ciechanover et al. in 2004 for their discovery of ubiquitin-mediated protein breakdown processes. Professors Raymond J. Deshaies and Craig M. Crews suggested PROTAC in 2001 as a way to induce in vivo protein degradation using small molecule compounds. When the tiny molecule enters the body, the affinity between the ligand and the protein can bring the target protein and the E3 ubiquitinase close together, allowing the target protein to be ubiquitinated and modified in vivo before being detected and degraded by the proteasome.

Compared to traditional small molecule inhibitors, monoclonal antibodies, siRNA, and CRISPR, the advantages of PROTAC molecules include:

1. Targeted degradation of "non-druggable proteins" and drug-resistant proteins in the body
2. Multiple drug delivery methods (oral, injection, perfusion, slow release, etc.)
3. Pass the blood brain barrier
4. Potential for tissue targeting
5. The compound can be widely distributed in vivo.

Previously, a PROTAC molecule known as MZ1 was found to be capable of mediating the degradation of the BET family protein BRD4 via VHL. Another BET inhibitor known as MT1 was found to bind to two BRD4 proteins. The researchers created a trivalent molecule with two binding domains for binding to BET proteins and one binding domain for binding to E3 ubiquitin ligase based on the crystal structure of BRD4-MZ1-VHL.

After screening, the researchers discovered SIM1, a trivalent PROTAC molecule, which, when compared to the existing bivalent PROTAC molecule MZ1, demonstrated a 300-fold increase in the activity of degrading BRD2 protein.

The researchers determined that the development of a stable ternary complex of PROTAC molecules with target proteins and E3 ligase is essential for improving protein degradation efficiency. This research demonstrates that trivalent PROTAC molecules can efficiently build stable ternary complexes and boost protein degradation efficiency by improving the molecules' affinity and cooperativity.

However, chemical synthesis is more challenging for the trivalent PROTAC molecule, and its cell permeability and pharmacokinetic profile may be compromised due to its increased molecular weight. This study, on the other hand, demonstrates that these obstacles can be overcome. Although less cell-permeable than the divalent molecule, the trivalent PROTAC molecule SIM1 has superior cellular activity and an appropriate pharmacokinetic profile in animals.

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