ASCO 2020: Therapeutic Approaches to Protein Degradation: PROTACs and E3 Ligase Modulation
The basic mechanism underlying these therapies is ubiquitin-mediated protein degradation. Ubiquitin is a highly conserved protein that serves to either label proteins for degradation or facilitates protein-protein interactions. The ubiquitin/proteasome pathway utilizes three sequential enzymes: E1, E2, and E3. First, the E1 ubiquitin-activating enzyme receives a ubiquitin molecule and transfers it to an E2 ubiquitin-conjugating enzyme. Then, with the help of the E3 complex, a lysine molecule on the target protein has the ubiquitin molecule conjugated to it. A single ubiquitin molecule is insufficient for proteasomal targeting, and so ubiquitin is added sequentially to build a poly-ubiquitin chain. This is then recognized by the proteasome. The target protein is unwound and then passes through the central channel of the proteasome, which contains proteases that degrade the target protein.
In abstract 3500, the authors studied ARV-110, an androgen receptor targeting proteolytic targeting chimera (PROTAC). This links the AR to the target E3 ligase, leading to polyubiquitination and degradation. A PROTAC consists of (1) a protein-ligand domain that targets the protein of interest, (2) a linker region that serves to properly orient the target protein, and the E3 ubiquitin ligase, and (3) a ligase ligand which recruits a specific E3 ubiquitin ligase. In abstract 3501, the investigators studied avadomide, which is a molecule that modulates the function of the CRBN E3 ubiquitin ligases.
With regard to the PROTAC ARV-110, there are several advantages and disadvantages to consider in PROTAC therapy. PROTACs have good absorption, distribution, metabolism, and elimination. They can be recycled such that they lead to the degradation of many target molecules. Additionally, they are less susceptible to mutation-directed mechanisms of drug resistance. Disadvantages of PROTACs include difficulty in design and synthesis, their large molecular weight, possible off-target effects, and the possibility that the intended E3 ubiquitin ligase is differentially expressed in the cancer being treated.
Overall, despite the challenges in design, protein degradation is a promising therapeutic strategy in cancer medicine, and additional data is needed to build on the early phase clinical trial data presented in Abstracts 3500 and 3501.
Presented by: Edward Yeh, MD, Professor of Medicine and Director of the Center for Precision Medicine, University of Missouri School of Medicine, Columbia, Missouri
Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 American Society of Clinical Oncology virtual annual meeting (#ASCO20), May 29th-May 31st, 2020