Proteolysis Targeting Chimera’s (PROTAC’s) Path from Innovation to Therapeutic Development: Insights from the Gartner Hype Cycle

What is Gartner Hype Cycle

The Gartner Hype Cycle is a conceptual graphical model, developed by the research and advisory firm Gartner, that illustrates the maturity, adoption, and social application of specific technologies over time (1). The Gartner Hype Cycle progresses through five key phases (Fig. 1):

1. Innovation Trigger: A potential breakthrough emerges, attracting media interest but often without resulting in usable products.
2. Peak of Inflated Expectations: Publicity-driven enthusiasm leads to unrealistic expectations.
3. Trough of Disillusionment: Interest wanes as implementations fail to deliver on initial promises.
4. Slope of Enlightenment: The technology’s benefits become clearer, and improved products begin to emerge.
5. Plateau of Productivity: Mainstream adoption takes off, establishing the technology’s market relevance.

Gartner Hype Cycle in PROTAC (Proteolysis Targeting Chimera) Drug Development

When applied to emerging drug discovery and therapeutic modalities like Targeted Protein Degradation (TPD), PROTACs (Proteolysis Targeting Chimeras), molecular glues, and LyTACs (Lysosome-Targeting Chimeras), the Gartner Hype Cycle helps contextualize both the potential and challenges associated with these technologies as they move through their innovation lifecycles. The details of PROTAC technologies are available here (click). Figure 1 illustrates the integration of PROTACs with the five phases of the Gartner Hype Cycle.

Fig. 1: Gartner hype cycle in PROTAC drug development

Timeline of the Rapid Progress of PROTAC Technology

The timeline (Table 1) highlights the rapid progress of PROTAC technology from an academic concept to a clinically-validated therapeutic modality over about two decades. Each step built on previous advances to expand the capabilities and applications of targeted protein degradation. Please note that this timeline is a rough estimation and not an exhaustive list.

Table 1: PROTAC Development Timeline

Mapping PROTAC Technology Progress Through the Five Phases of the Gartner Hype Cycle

The five phases of the Gartner hype cycle for PROTAC technology are summarized in Fig. 1.

1. Innovation Trigger

The innovation of PROTACs began with the seminal work by Sakamoto et al. in 2001 (2), introducing the concept of targeted protein degradation via ubiquitin-proteasome pathways using bifunctional molecules. Early PROTACs, such as Protac-1, demonstrated the feasibility of redirecting E3 ubiquitin ligases to specific target proteins for degradation. Protac-1, a chimeric molecule, was designed to connect methionine aminopeptidase-2 (MetAP-2) to the Skp1-Cullin-F box (SCF) complex, a key ubiquitin ligase that tags proteins for degradation. Protac-1 consists of two parts: one binds to MetAP-2 through ovalicin, and the other interacts with the F-box protein β-TRCP. This interaction facilitates the ubiquitination and subsequent degradation of MetAP-2.

This innovation phase excited the scientific community, as it provided a novel approach to target proteins traditionally considered “undruggable,” such as transcription factors and scaffolding proteins. The potential implications for diseases such as cancer, neurodegeneration, and inflammatory conditions fueled early enthusiasm.

2. Peak of Inflated Expectations

As PROTAC technology advanced, it entered the peak of inflated expectations phase. This period was characterized by growing excitement and optimism about the potential of PROTACs to revolutionize drug discovery. One key development during this phase was the creation of small molecule-based PROTACs, which replaced peptide-based E3 ligase recruiters with more drug-like structures. For example, Schneekloth et al. in 2004 (30) demonstrated the use of PROTACs to induce the degradation of green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR) in cultured cells. This study represented the first in vivo examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation. The ability of PROTACs to target proteins previously considered undruggable further fueled enthusiasm. Researchers began exploring PROTACs for a wide range of targets, including transcription factors and scaffolding proteins.

Between 2005 and 2010, the interest in PROTACs soared. Researchers expanded PROTAC applications to degrade clinically relevant targets like androgen and estrogen receptors implicated in prostate and breast cancers. Studies like those by Schneekloth et al. demonstrated PROTAC-mediated degradation of the androgen receptor, illustrating the potential of this technology to revolutionize oncology (4).

Commercial interest also grew, with biotech companies entering the field. However, limitations such as poor cell permeability, low stability, and challenges in designing effective bifunctional molecules tempered some expectations. These obstacles hinted at the gap between laboratory feasibility and real-world therapeutic application.

3. Peak of Inflated Expectations

As with many emerging technologies, PROTACs encountered challenges that led to a period of disillusionment. Some of the initial hurdles included:

1. Off-target effects: Early PROTACs sometimes exhibited unintended degradation of non-target proteins.
2. Limited oral bioavailability: The relatively large size of PROTAC molecules posed challenges for oral administration.
3. Incomplete understanding of ternary complex formation: The precise mechanisms governing the formation of the protein of interest-PROTAC-E3 ligase complex were not fully elucidated.

These challenges tempered some of the initial excitement and highlighted the need for further research and optimization. The initial enthusiasm faced setbacks as practical challenges emerged. Early-generation PROTACs suffered from pharmacokinetic issues, poor bioavailability, and difficulties in crossing the cell membrane. Furthermore, the complexity of bifunctional molecule design led to a realization that large-scale therapeutic application required substantial optimization. For example, while targeting androgen and estrogen receptors showed promise, the transition from proof-of-concept studies to robust preclinical models highlighted the limitations in achieving target specificity and reducing off-target effects. Funding and collaboration efforts saw fluctuations as stakeholders reassessed the feasibility of the technology.

4. Slope of Enlightenment

The period from 2015 onward marked a resurgence in PROTAC interest, driven by advancements in medicinal chemistry and high-throughput screening technologies. The development of more cell-permeable and stable PROTACs, such as those incorporating E3 ligases like Cereblon and VHL, demonstrated improved efficacy.
Academic and industrial partnerships proliferated, with companies like Arvinas and Kymera Therapeutics advancing PROTACs into clinical trials. For example, ARV-110, a PROTAC targeting the androgen receptor, entered clinical evaluation for prostate cancer, marking a significant milestone (31).

As researchers addressed the initial challenges, PROTACs began to ascend the slope of enlightenment. This phase has been marked by significant advancements in PROTAC design and a deeper understanding of their mechanisms of action. One notable example is the development of ARV-110, a PROTAC targeting the androgen receptor (AR) for the treatment of prostate cancer. ARV-110 demonstrated efficacy in degrading AR in patient xenografts harboring mutations that confer resistance to traditional AR inhibitors (32). This demonstrated the potential of PROTACs to overcome resistance mechanisms that limit the efficacy of conventional small molecule inhibitors. Another important development was the creation of PROTACs specifically targeting mutant oncoproteins. For instance, researchers developed a PROTAC capable of selectively degrading mutant KRAS G12C/G13D while sparing wild-type KRAS (33). This ability to discriminate between mutant and wild-type proteins highlights the potential for PROTACs to achieve high specificity and potentially reduce off-target effects.

5. Plateau of Productivity

As PROTACs continue to mature, they are approaching the plateau of productivity. This phase is characterized by increasing clinical validation and the emergence of real-world applications. Several PROTACs have now entered clinical trials, providing crucial data on their safety and efficacy in humans (Table 2).

Table 2: Few PRTOACs and molecular glues in clinical trials

These clinical advancements are paving the way for broader adoption of PROTAC technology in drug development pipelines.

Today, PROTAC technology has reached a phase of productive application, with several candidates in clinical trials targeting oncological and autoimmune diseases. The ability to degrade specific proteins rather than merely inhibit their function offers profound therapeutic advantages, including overcoming drug resistance in cancer. Moreover, the refinement of linker chemistry and advancements in understanding the structural biology of E3 ligase-target complexes have catalyzed progress. The success of these endeavors exemplifies the therapeutic maturation of PROTACs and their potential to address previously unmet medical needs.

Gartner Hype Cycle for Various Targeted Protein Degradation (TPD) Technologies

Table 3: Gartner hype cycle placement of targeted protein degradation (TPD) technologies other than PROTACs.  The details of each TPD technology are available here: https://www.marinbio.com/services/targeted-protein-degradation/.

Table 3: Gartner hype cycle placement of targeted protein degradation (TPD) technologies other than PROTACs

Future Directions

Several real-world applications highlight the maturity of PROTACs:
1. Oncology: The degradation of BET family proteins and androgen receptors in resistant prostate cancers has shown promise in overcoming traditional therapeutic limitations.
2. Neurodegeneration: PROTACs targeting tau proteins and α-synuclein offer novel approaches for conditions like Alzheimer’s and Parkinson’s diseases.
3. Inflammatory Diseases: By targeting cytokine signaling pathways, PROTACs hold potential for autoimmune disease modulation.
Future directions include expanding the range of E3 ligases, improving tissue-specific delivery, and exploring combination therapies.

Conclusion

Targeted protein degradation technologies, including PROTACs, molecular glues, AbTACs, and LyTACs, exemplify the stages of the Gartner Hype Cycle. Their journey from groundbreaking innovation through periods of recalibrated expectations to sustained productivity reflects the broader process by which complex technologies mature. Though significant hurdles remain, ongoing advancements suggest that targeted protein degradation will continue to progress toward becoming an established component of the therapeutic landscape, offering novel solutions for previously intractable diseases.

Appendix

MarinBio Publications and Presentations on Gene Therapy

American Society of Hematology (ASH) Annual Meeting 2024

Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager

Targeted Protein Degradation (TDP) Assay Services Offered by MarinBio

Related Articles/Blogs

PROTACs for Innovative Drug Development: Current Trends and Future Prospects

Advancing PROTAC Therapeutics: Potency Assays for FDA Compliance

Cutting-Edge PROTACs: Ready to Transform Clinical Oncology

Recent PROTAC Patent Publications and Target Proteins

Proteolysis-Targeting Vaccines (PROTAVs): A Novel Approach in Cancer Immunotherapy

Expanding the Toolbox of PROTAC Degraders with Covalent Ligands for Genetically Validated Targets

Researchers Unveil New Insights into Trivalent PROTACs and the Hook Effect

References

1. Spotlight on 2024 Gartner Hype Cycle™ for Emerging Technologies. 
2. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation.
3. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation.
4. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.
5. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.
6. Protacs for treatment of cancer.
7. Catalytic in vivo protein knockdown by small-molecule PROTACs.
8. . Arvinas Announces Initiation of Patient Dosing in the First Phase 1 Clinical Trial of PROTAC™ Protein Degrader, ARV-110.
9. Cutting-Edge PROTACs: Ready to Transform Clinical Oncology
10. PROTACs for Innovative Drug Development: Current Trends and Future Prospects.
11. Recent PROTAC Patent Publications and Target Proteins.
12. PROTAC Targeted Protein Degraders Market Clinical Trials Insight to 2027 – Emerging PROTAC Therapeutics Set to Revolutionize Targeted Protein Degradation in Clinical Trials.
13. Arvinas Releases Updated Dose Escalation Data from Clinical Trial of PROTAC® Protein Degrader ARV-110 in Patients with Metastatic Castration-Resistant Prostate Cancer.      
14. Arvinas Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Corporate Update.
15. Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC® Protein Degrader ARV-471. 
16. Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CC-94676 in Subjects With Metastatic Castration-Resistant Prostate Cancer. 
17. Kintor Advances With GT20029 Clinical Trials for Hair Loss.
18. Hinova Announces First Patient Dosed in a Phase I Clinical Trial of HP518, an Orally Bioavailable Chimeric Degrader Targeting Androgen Receptor for Prostate Cancer Treatment.
19. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role.
    20. Dialectic Therapeutics Announces First-in-Human Dose in Phase 1 Clinical Trial Evaluating DT2216, its First Generation Antiapoptotic Protein Targeted Degradation (APTaD™) Compound, in Patients with Relapsed or Refractory Malignancies. 
20. C4 Therapeutics Announces Positive Data from CFT7455 Phase 1 Trial in Relapsed/Refractory Multiple Myeloma. 
21. C4 Therapeutics Announces First Patient Dosed in Phase 1/2 Clinical Trial Evaluating CFT8634, an Orally Bioavailable BiDAC™ Degrader for the Treatment of Synovial Sarcoma and SMARCB1-null Tumors. 
22. Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. 
23. CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.
24. Dose- and Schedule-Dependent Immunomodulatory Effects of the Novel Celmod Agent CC-92480 in Patients with Relapsed/Refractory Multiple Myeloma. 
25. CC-99282 is a Novel Cereblon (CRBN) E3 Ligase Modulator (CELMoD) Agent with Enhanced Tumoricidal Activity in Preclinical Models of Lymphoma. 
26. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN.
27. Summary of Molecular Glues Approved or in Clinical Trial.
28. Molecular glue degrader for tumor treatment. 
29. Chemical genetic control of protein levels: selective in vivo targeted degradation.
30. PROTAC targeted protein degraders: the past is prologue.
31. Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader.
32. Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs.