Last week marked a major milestone in small-molecule drug discovery with the first FDA approval of a proteolysis targeting chimera (PROTAC). After a modest but successful phase 3 clinical trial demonstrated a 2.9 month improvement in median progression free survival1 for a type of advanced breast cancer1, the FDA has approved Veppanu (vepdegestrant), co-developed by Arvinas and Pfizer, as the first PROTAC protein degrader therapy2. So what is a PROTAC?
Traditional small-molecule drugs operate by selectively binding to a target, typically a protein, and modifying its function. Broadly, these modifications can be categorized as inhibitory or activating. Drugs that function as inhibitors serve to reduce the function of a target, often an enzyme, receptor, transporter, or signalling protein. For example, if an enzyme is overactive in cancer, inflammation, or viral replication, an inhibitor can slow or block that disease-driving process. In contrast, an activator increases the function of a target. Activators are used when a disease involves insufficient activity, loss of signalling, weak enzyme function, or impaired cellular response. Activators can operate by increasing enzyme turnover, stabilizing an active protein conformation, enhancing receptor signalling, or boosting downstream pathway output.
Since the early 2000s, however, an advanced wave of targeted protein degradation therapies have been under development3. Rather than inhibiting a target, targeted degradation therapies operate by leveraging the body’s natural cellular machinery, the proteasome, to degrade the target.
PROTACs consist of three parts: an E3 ligand, a linker, and a warhead that attaches to a protein of interest (POI) 4. At a high-level, a PROTAC aims to recruit a protein called an E3 ligase to be within close proximity to the POI. This is achieved by creating a bridge between the E3 ligase and the POI using the E3 ligand, a warhead that attaches to the POI, and a linker which bridges them. The E3 ligase mediates the transfer of ubiquitin to the POI, and these ubiquitin tags mark the POI for degradation by the proteasome, a complex which degrades proteins4. A figure from a recent review paper4 illustrates:
But if we have inhibitors, which ostensibly reduce the function of the target, why would we want to go to the trouble of degrading it entirely? PROTACs come with a number of advantages over traditional inhibitors. For example, in certain cases, the presence or accumulation of a protein is what contributes to disease pathology. Thus, PROTACs are useful when when the target has nonenzymatic/scaffolding functions that an inhibitor may not block. Moreover, PROTACs can work on proteins that are hard to inhibit. For example, some proteins lack a deep, druggable active site. In contrast, to be effective, a PROTAC only needs to bind the target somewhere productively; the binding event does not necessarily have to inhibit function directly.
Last week’s approval of Veppanu demonstrates that PROTACs are clinically viable drugs, and more generally signals that targeted protein degradation has a future in the quest to combat disease. Similar therapeutics such as ATTECs, AUTACs and LYTACs, which hijack cellular autophagy machinery via the lysosome5, now seem increasingly promising as future modalities for small-molecule drugs. Similarly, this news should serve as encouragement that other advanced small-molecule therapeutics such as molecular glues6 may also not be too far from the clinic.
References
- Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer, New England Journal of Medicine (Campone et al, 2025)
- Arvinas Announces FDA Approval of VEPPANU (vepdegestrant)
- Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation, Proceedings of the National Academy of Sciences (Sakamoto et al, 2001)
- PROTAC targeted protein degraders: the past is prologue, Nature Reviews Drug Discovery, (Békés et al, 2022).
- Emerging New Concepts of Degrader Technologies, Trends in Pharmacological Science, (Ding et al, 2020)
- Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Biochemistry, (Sasso et al, 2022)
Footnotes
- Relative to the hormone treatment fulvestrant. ↩︎
