Traditional drug development depends upon the discovery of a small molecule that binds to the active site of a protein of interest (POI) and functionally blocks its activity. However, this type of ‘occupancy-driven’ pharmacology is only suitable for a narrow range of applications, as it requires the target to have both a well-defined binding pocket and established enzymatic activity. Consequently, an estimated 80-90% of the human proteome – including transcription factors, scaffolding proteins, and many other clinically relevant targets – is considered ‘undruggable’ by conventional strategies.

Targeted protein degradation (TPD) is a powerful biological modality that overcomes these limitations by leveraging the cell’s endogenous proteolytic machinery to degrade, rather than simply inhibit, a POI. One of the most popular TPD technologies is that of proteolysis-targeting chimeras, or PROTACs. Simply put, a PROTAC consists of two ligands joined by a linker region. While one ligand engages the POI, the other recruits an E3 ubiquitin ligase. Once brought within sufficient proximity, the E3 ligase polyubiquitinates the POI, inducing its degradation by the proteasome. In this way, PROTACs and other TPD strategies physically eliminate target proteins, rather than simply inhibiting their enzymatic function. This is particularly important given that many enzyme families – including kinases and poly(ADP-ribose) polymerases (PARPs) – are known to play critical scaffolding and signaling roles in addition to their catalytic functions (Kim et al., 2023). The advantages of target depletion over inactivation are also highlighted in the context of cancer and treatment resistance. For example, treatment with RAF kinase inhibitors has been shown to promote tumor growth in some contexts by altering RAF localization and interaction patterns even while blocking its enzymatic activity (Hatzivassiliou et al., 2010).

The most transformative aspect of TPD, however, lies in its ‘event-driven’ pharmacology. While conventional ligands must engage with and inhibit a specific active site, binding of a TPD ligand anywhere on the POI is sufficient to induce degradation. As a result, TPD approaches can be readily applied to otherwise-challenging targets, such as proteins with broad, shallow active sites, or those with ‘smooth’ surfaces and few small-molecule binding pockets. Furthermore, because these degraders are catalytic and recyclable (i.e., upon POI degradation, the degrader dissociates and is free to engage with a new target molecule), they can be administered at much lower doses than traditional inhibitor drugs, and less frequent administration is required. TPD approaches are thought to be less susceptible than traditional inhibitors to the development of ‘escaping’ mutations (Lu et al., 2020) and have been successfully used to overcome acquired drug resistance in cancer and viral contexts (Sun et al., 2019; de Wispelaere et al., 2019). At the same time, TPD-based strategies exhibit exquisite specificity and selectivity, as demonstrated by the specific degradation of the transcriptional regulator CDK9 with no effect on other CDK family members (Olson et al., 2018).

Given these advantages, it should come as no surprise that PROTACs and other TPD strategies have attracted significant clinical attention. In 2019, the first PROTAC degraders – ARV-471 and ARV-110 –entered clinical trials, representing a watershed moment for TPD therapeutics. ARV-471, also known as vepdegestrant, is a PROTAC degrader targeting the estrogen receptor (ER), developed by Arvinas and Pfizer to treat patients with ER+/HER2- breast cancer. In a Phase 1/2 study (NCT04072952), vepdegestrant showed promising results, both as a monotherapy and in combination with palbociclib (Hamilton et al., 2022), and Phase 3 trials in patients with advanced metastatic breast cancer are ongoing (NCT05654623; Campone et al., 2023). ARV-110, also known as bavdegalutamide, was developed by Arvinas to target and degrade the androgen receptor (AR) in patients with metastatic castration-resistant prostate cancer (mCRPC) (Gao et al., 2022). Phase 1 trials (NCT03888612) established the drug’s safety and tolerability, while ongoing Phase 2 trials continue to characterize its effectiveness and pharmacodynamics.

Bavdegalutamide has been followed in the clinical pipeline by a number of additional AR-targeting PROTACs, including compounds developed by Arvinas (ARV-766; NCT05067140), BMS/Celgene (CC-94676; NCT04428788), and Hinova (HP518; NCT06155084) (Jia & Han, 2023). Currently in Phase 1 trials (NCT05225584), Kymera Therapeutics has developed a STAT3 degrader, KT-333, for the treatment of relapsed/refractory lymphomas, leukemias, and solid tumors (Starodub et al., 2022). Another promising degrader, NX-2127, was developed by Nurix Therapeutics to target Bruton’s tyrosine kinase (BTK) for the treatment of B-cell malignancies (Mato et al., 2022); following a partial hold, Phase 1 clinical trials were resumed in March 2024 (NCT04830137).

Early PROTAC therapeutics were designed to target well-studied proteins with existing pharmacological inhibitors, enabling their comparative safety and efficacy to be evaluated. Now that their general utility and tolerability has been established, researchers have begun to apply these technologies to novel targets and diseases for which conventional treatments are insufficient or wholly unavailable. In particular, interest has arisen in the application of PROTACs to proteopathies and other neurodegenerative diseases. In February 2024, Arvinas initiated Phase 1 trials of ARV-102, the first PROTAC treatment for neurodegenerative diseases. This drug targets the kinase LRRK2, associated with Parkinson’s disease and progressive supranuclear palsy, and was shown in primate studies to reduce LRRK2 levels in the cortex, striatum, and cerebellum by over 85% (Arvinas, 2024). PROTACs targeting Tau for the treatment of frontotemporal dementia, Alzheimer’s disease, and other tauopathies have also shown positive preclinical results, with the compound QC-01-175 significantly reducing levels of aberrant Tau in patient-derived neurons (Lu et al., 2018; Silva et al., 2022). Other groups have targeted Alpha-synuclein as a treatment for Parkinson’s disease and other synucleinopathies, both alone (Tong et al., 2023) and in combination with Tau (Zhu et al., 2024), mutant HTT protein as a treatment for Huntington’s disease (Li et al., 2019), and TDP-43 as a treatment for amyotrophic lateral sclerosis (ALS) (Tseng et al., 2023).

Another category of innovative degrader-based therapeutics applies PROTAC technology to exogenous targets for the treatment of infectious diseases. The telaprevir-based degrader DGY-08-097, for example, degrades the protease of the hepatitis C virus (HCV) and exhibits potent anti-viral activity, even in cases where mutations have rendered the HCV protease resistant to conventional inhibitors (de Wispelaere et al., 2019). Other groups have leveraged PROTACs against SARS-CoV-2 and other coronaviruses (Desantis et al., 2021; Alugubelli et al., 2024), influenza viruses (Li et al., 2022), and HIV (Emert-Sedlak et al., 2024). BacPROTACs, which effect degradation of microbial targets through the bacterial ClpCP protease (Morreale et al., 2022), are currently being developed for the treatment of multi-drug resistant tuberculosis (Won et al., 2024; Junk et al., 2024). Preliminary reports have even suggested the utility of “TrypPROTACs” in treating trypanosomiasis and other parasitic infections (Danazumi et al., 2023; Ishii & Akiyoshi, 2022).

Since their initial description almost 25 years ago, PROTACs have proven their worth as potent and versatile therapeutic agents. Their ‘event-driven’ mechanism of action enables PROTACs to function at much lower doses than traditional drugs while retaining stringent selectivity, minimizing toxicity and off-target effects. Because PROTACs degrade rather than inhibit, they can be flexibly applied to virtually any cellular target, agnostic to enzymatic activity. Furthermore, PROTACs are less susceptible to resistance mechanisms, making them particularly well-suited for the treatment of drug-resistant cancers, antibiotic-resistant bacterial infections, and other challenging applications. Thanks to their powerful advantages, PROTAC and other TPD technologies have revolutionized the pharmaceutical landscape, and a wealth of promising preclinical data suggests that they will continue to do so in the years to come.

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