Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders

by Selleckchem | Sep 16 2023

Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition. The three-way interactions among the HBF, the target POI, and the ligase-including the protein-protein interaction between the POI and the ligase-contribute to the stability of the ternary complex, manifested as positive or negative binding cooperativity in its formation. How such cooperativity affects HBF-mediated degradation is an open question. In this work, we develop a pharmacodynamic model that describes the kinetics of the key reactions in the TPD process, and we use this model to investigate the role of cooperativity in the ternary complex formation and in the target POI degradation. Our model establishes the quantitative connection between the ternary complex stability and the degradation efficiency through the former's effect on the rate of catalytic turnover. We also develop a statistical inference model for determining cooperativity in intracellular ternary complex formation from cellular assay data and demonstrate it by quantifying the change in cooperativity due to site-directed mutagenesis at the POI-ligase interface of the SMARCA2-ACBI1-VHL ternary complex. Our pharmacodynamic model provides a quantitative framework to dissect the complex HBF-mediated TPD process and may inform the rational design of effective HBF degraders.

Comments:

The passage you provided describes a research study that aims to investigate the role of cooperativity in the formation of ternary complexes involved in targeted protein degradation (TPD). TPD is a promising approach for modulating disease-associated proteins using heterobifunctional (HBF) molecules that can induce the degradation of specific target proteins.

The researchers developed a pharmacodynamic model to describe the kinetics of key reactions in the TPD process. This model allows them to investigate how cooperativity, which refers to the interactions among the HBF, the target protein of interest (POI), and the E3 ligase, affects the stability of the ternary complex and subsequently influences the degradation of the POI.

The model establishes a quantitative connection between the stability of the ternary complex and the efficiency of degradation. It does so by considering the effect of the ternary complex stability on the rate of catalytic turnover, which is a measure of how quickly the target protein is degraded.

Additionally, the researchers developed a statistical inference model to determine the cooperativity in intracellular ternary complex formation using cellular assay data. This model allows them to quantify the change in cooperativity resulting from specific modifications at the interface between the POI and the ligase.

By combining the pharmacodynamic model and the statistical inference model, the researchers aim to gain a deeper understanding of the complex TPD process mediated by HBFs. This understanding may then be used to inform the rational design of effective HBF degraders for therapeutic purposes.

Overall, the study contributes to our knowledge of how cooperativity influences the formation and stability of ternary complexes involved in targeted protein degradation, providing insights that could potentially aid in the development of novel therapeutic strategies.