Proteolysis Targeting Chimeras (PROTACs) are a novel class of bifunctional molecules designed to selectively degrade disease-causing proteins. A PROTAC typically consists of three components: a ligand that binds the protein of interest (POI), a ligand that recruits an E3 ubiquitin ligase, and a linker connecting the two. This structure enables PROTACs to harness the body's natural ubiquitin-proteasome system (UPS) to tag and degrade target proteins, offering a promising new approach to drug discovery.

Currently, while no PROTAC-based therapies have yet reached the market, over 30 PROTAC drug candidates are actively being evaluated in clinical trials. These investigational treatments target a diverse array of proteins, including the androgen receptor (AR), estrogen receptor (ER), Bruton's tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase 4 (IRAK4). The potential applications span various diseases, such as hematological malignancies, solid tumors, and autoimmune disorders.

Table 1. PROTACs in Clinical Trials for Diseases

PROTACs in Phase 3 Clinical Trials

Three PROTACs have advanced to Phase 3 clinical trials: Arvinas/Pfizer's ARV-471 (targeting ER), Bristol Myers Squibb's BMS-986365 (targeting AR), and BeiGene's BGB-16673 (targeting BTK).

Vepdegestrant（ARV-471）

Vepdegestrant (ARV-471) is the world's first oral PROTAC molecule to advance into Phase III clinical trials. Developed as a potential first-in-class oral PROTAC degrader, vepdegestrant is designed to harness the body's natural protein disposal system to specifically target and degrade the ER. In February 2024, the U.S. Food and Drug Administration (FDA) has granted Vepdegestrant Fast Track designation for monotherapy in the treatment of adults with ER+/HER2- advanced or metastatic breast cancer previously treated with endocrine-based therapy.

In March 2025, Arvinas and Pfizer recently shared results from the Phase III VERITAC-2 clinical trial (NCT05654623), which compared vepdegestrant monotherapy to fulvestrant in adults with ER-positive, HER2-negative advanced or metastatic breast cancer whose disease had progressed after treatment with CDK4/6 inhibitors and endocrine therapy.

The trial met its primary endpoint in patients with ESR1 mutations, showing a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to fulvestrant. The results exceeded the target hazard ratio of 0.60 in this group. However, the trial did not reach statistical significance in the overall intent-to-treat (ITT) population. [2]

At the time of analysis, overall survival (OS) data was still immature, with fewer than 25% of the required events recorded. The study will continue tracking OS as a key secondary endpoint. Full results from VERITAC-2 are expected to be presented at a medical conference later this year and will be shared with global health authorities to support potential regulatory submissions.

Following the mixed results from the Phase III VERITAC-2 trial, Arvinas provided an update on the vepdegestrant program in its Q1 results. As part of a strategic shift, Arvinas and Pfizer have decided to cancel two planned Phase III trials—one evaluating vepdegestrant with Pfizer’s investigational CDK4 inhibitor atirmociclib as a first-line treatment, and another exploring a second-line combination of vepdegestrant with a CDK4/6 inhibitor. [3]

Despite these changes, the partners are moving forward with plans to submit vepdegestrant for approval as a second-line monotherapy in the second half of the year.

BMS-986365（CC-94676）

Recently, the U.S. clinical trial registry platform ClinicalTrials.gov announced that Celgene, a subsidiary of Bristol Myers Squibb (BMS), has officially launched a Phase III clinical trial for its investigational drug BMS-986365 (also known as CC-94676). This marks the second PROTAC drug worldwide to enter Phase III trials and the first AR-targeting PROTAC to reach this stage.

BMS-986365 is a potent ligand-directed degrader (LDD) that promotes CRL4^CRBN E3 ubiquitin ligase–dependent ubiquitination and degradation of the androgen receptor (AR). It effectively induces rapid and deep degradation of both wild-type and mutant AR in the cytoplasm and nucleus. Compared to the AR antagonist enzalutamide, BMS-986365 demonstrates approximately 100 times greater potency in suppressing AR-driven gene transcription and shows 10- to 120-fold higher efficacy in inhibiting AR-dependent proliferation in various prostate cancer cell lines.

In January 2024, BMS presented Phase I clinical data on BMS-986365 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) at the ASCO Genitourinary Cancers Symposium (ASCO GU 2024). The results showed a dose-dependent increase in the proportion of patients achieving a ≥30% decline in PSA levels (PSA30) with twice-daily doses of 400–900 mg. In the full-dose group, 34% (23/68) of patients achieved PSA30. Among patients receiving the 900 mg twice-daily dose, 55% (11/20) achieved PSA30, 35% (7/20) achieved PSA50, and 10% (2/20) achieved PSA90. Additionally, 45% (9/20) of patients in this group had no disease progression at 6 months.

In January 2025, BMS released an updated analysis of the same study. Among 60 patients treated with 400–900 mg twice daily, 32% (19/60) achieved PSA50, including 10 patients from the 900 mg group. The median radiographic progression-free survival (rPFS) was 6.3 months overall, and 8.3 months in the 900 mg group. Notably, treatment-naïve patients had a longer median rPFS compared to previously treated patients (16.5 vs 5.5 months). [5]

Figure 1. rPFS in part B, in patients treated at b.i.d. doses. [5]

BGB-16673

In April 2025, ClinicalTrials.gov listed the launch of the first Phase III clinical trial of BGB-16673, a BTK-targeting PROTAC developed by BeiGene. This marks the first BTK PROTAC to enter Phase III, and the third PROTAC molecule worldwide to reach this stage.

The ongoing randomized, open-label Phase III study (n=250) aims to evaluate the efficacy and safety of BGB-16673 versus investigator’s choice of therapy (idelalisib plus rituximab or bendamustine plus rituximab or venetoclax plus rituximab retreatment) in patients with chronic lymphocytic leukemia (CLL) who have previously received both BTK and BCL-2 inhibitors. The primary endpoint is progression-free survival (PFS) at month 36, as assessed by an Independent Review Committee (IRC).

At the ASH 2024 Annual Meeting, BeiGene shared Phase I data from the CaDAnCe-101 study in relapsed/refractory CLL. Among 49 treated patients, the overall response rate (ORR) reached 78% (38/49), with the 200 mg dose group achieving an ORR of 94%.  [6]

BGB-16673 has also shown promise in other hematologic malignancies. In the same Phase I trial:

• •Waldenström's macroglobulinemia (WM): ORR of 90% in 21 patients [7]
• •Follicular lymphoma (FL): ORR of 50% in 8 patients [8]
• •Marginal zone lymphoma (MZL): ORR of 67% in 8 patients [8]

These results highlight BGB-16673 as a potentially first-in-class BTK degrader with broad activity across B-cell malignancies.

Conclusion

It has been more than 20 years since the concept of PROTAC was first introduced. As an emerging drug discovery technology, PROTACs have gained significant attention from both academia and the pharmaceutical industry for their potential to target previously “undruggable” proteins and overcome drug resistance.

However, despite the promise, PROTAC drug development also faces considerable challenges. Many PROTAC molecules have high molecular weights, making them difficult to crystallize, poorly soluble, and poorly permeable. Additionally, oral bioavailability remains low for several candidates, posing further obstacles for clinical translation and commercial success.

References:
[1] Zhong, G., Chang, X., Xie, W. et al. Targeted protein degradation: advances in drug discovery and clinical practice. Sig Transduct Target Ther 9, 308 (2024). https://doi.org/10.1038/s41392-024-02004-x 
[2] https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-positive-topline-results-phase-3  
[3] https://www.fiercebiotech.com/biotech/arvinas-lays-33-staff-axes-pfizer-partnered-phase-3-trials-after-seeing-mixed-data
[4] https://ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.134 First-in-human phase 1 study of CC-94676, a first-in-class androgen receptor (AR) ligand-directed degrader (LDD), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
[5] https://www.sciencedirect.com/science/article/pii/S0923753424040018 Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer
[6] https://ashpublications.org/blood/article/144/Supplement%201/885/530857/Preliminary-Efficacy-and-Safety-of-the-Bruton Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Results from the Phase 1 CaDAnCe-101 Study
[7] https://ashpublications.org/blood/article/144/Supplement%201/860/530753/Preliminary-Efficacy-and-Safety-of-the-Bruton Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory Waldenström Macroglobulinemia: Results from the Phase 1 CaDAnCe-101 Study
[8] https://ashpublications.org/blood/article/144/Supplement%201/1649/529309/Preliminary-Efficacy-and-Safety-of-the-Bruton Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory (R/R) Indolent NHL: Results from the Phase 1 CaDAnCe-101 Study