In this blog post, we use the term ‘PROTAC’ as the common abbreviation for the therapeutic modalities encompassed by PROteolysis TArgeting Chimera. PROTAC^® is a registered trademark of Arvinas.

Since early 2021, PROTAC technology has experienced exponential growth, pushing the boundaries of targeted protein degradation (TPD) and ushering a new chapter on new modality drug discovery. With more candidates entering clinical trials and expanding beyond oncology into neurodegenerative and rare diseases, researchers now face the dual challenge of the escalating complexities of data management and analysis while identifying new therapeutic candidates. The demand for novel modality literate informatics solutions has never been more critical.

As the field rapidly evolves, researchers are eager to seize exciting opportunities, but they must first tackle significant challenges—particularly in managing the complex research and data requirements that accompany this innovative approach to drug development.
 

5 Key Challenges in PROTAC Research:

1. Complex Research. The three-part structure of PROTACs and the nearly infinite possible variations introduce a level of complexity in production and testing that extends far beyond conventional small molecules. This complexity, coupled with bioavailability, permeability, and pharmacokinetic hurdles, makes advancing PROTAC technology from the lab to clinical trials a daunting task. 
2. New Ways of Thinking. Because the physicochemical properties of PROTAC molecules tend to break Lipinski’s Rule of 5, allowing for oral bioavailability, the field requires a shift in thinking to address the unique abilities and challenges these molecules present. From considering linker and ligand components to selecting E3 ligases (with more than 600 to choose from!), innovative design and optimization strategies are required for further development. 
3. Specialized Software. The unique nature of PROTAC research demands specialized tools and workflows. Scientists require integrated data management platforms to manage the multi-modal aspects of PROTAC and TPD research and manage vast amounts of data.
4. Communication and Collaboration. The multidisciplinary nature of PROTAC research requires seamless collaboration across various scientific disciplines. Efficient information sharing among team members is crucial yet challenging. Informatics tools need to enhance real-time communication and data sharing.
5. Data Analysis. PROTAC research generates massive volumes of data from diverse sources like HTS, HCS, and DMPK-PKPD assays. Breaking down data silos, ensuring accessibility, and integrating various data types pose significant challenges. 

In addition, there is a lack of approved drugs, which leads to difficulties in translating the technology to the clinic and expensive and complex lab work. These challenges are interrelated and emphasize the multi-layered complexity of PROTAC research. All this sets the stage for innovative solutions like advanced data management tools to drive progress in this field.
 

PROTAC Evolution: Expanding Beyond Oncology

While initially used for oncology, the potential of PROTACs is now being explored across a broader range of diseases. With more candidates entering clinical trials for conditions like Parkinson’s and Alzheimer’s, the prospect of new treatments is increasingly evident, reshaping drug discovery and opening doors to treating diseases once considered undruggable, such as:

• Huntington's disease: a neurodegenerative disorder caused by a mutant form of the huntingtin protein. PROTACs are being researched to degrade the toxic protein aggregates associated with the disease.
• Parkinson's disease: Alpha-synuclein, a protein linked to Parkinson's disease, has been challenging to target directly. PROTACs are being investigated to degrade this protein and potentially slow the disease's progression.
• Amyotrophic Lateral Sclerosis (ALS): PROTACs are being considered to target and degrade proteins such as TDP-43 and SOD1, which are implicated in ALS.

Some companies are advancing multiple PROTAC candidates through clinical trials. This table summarizes some of the most recent advances in PROTAC research. 

Other progress in PROTAC research set to expand therapeutic candidates include improvements in:

• Design strategies - including novel E3 ligase binders beyond the commonly used VHL and cereblon.
• Addressing bioavailability and pharmacokinetic challenges.
   

In addition to these improvements, there are also new developments in:

• Target selection - Understanding protein degradability and E3 ligase recruitment and proteome-wide degradability profiling techniques.
• Combination therapies – compounding PROTACs and other degraders with conventional therapies to improve treatment efficacy.
• Informatics & AI – using machine learning technology for PROTAC design and degradability predictions as well as the new specialized databases and computational tools for TPD research.

The Development of TPD Technologies:

PROTAC technology is not advancing in isolation. There is also remarkable progress across the broader spectrum of targeted protein degradation (TPD) approaches. For example:

• Molecular Glues: Once serendipitous discoveries, these are now being rationally designed, expanding their reach to various proteins and E3 ligases.
• LYTACs, AUTACs, and ATTECs: These novel modalities are progressing rapidly, with some entering preclinical stages.
• Emerging Modalities: Keep an eye on PHOTACs (light-activated PROTACs) and CLIPTACs (click-formed PROTACs), with additional molecules also pushing the boundaries of what's possible in TPD.

While a comprehensive exploration of the future of broad-spectrum TPD research is beyond the scope of this post, it's true the future is bright, and researchers still have significant challenges to fully realize these opportunities. 
 

The Future of TPD and PROTACs is a Collaborative Effort

The advancement of PROTAC and TPD technologies is proof of the power of collaboration. Partnerships between academic institutions and pharmaceutical companies are driving innovation, and ongoing discussions with regulatory agencies are shaping the preclinical and clinical development pathways for protein degraders.

Furthermore, these collaborations add powerful new platforms to the drug discovery toolbox. For instance, multiple pharma companies are working to combine TPD technology with antibody drug conjugates (ADCs) to form degrader antibody conjugates (DACs), which are an exciting new modality for cancer therapies.

The Role of Informatics in Advancing PROTAC and TPD Research

Informatics solutions play a central role in addressing the unique challenges of PROTAC and TPD research. By leveraging sophisticated informatics tools and workflows, scientists can effectively navigate the complexities, overcome the challenges in these research areas and avoid time-wasting distractions while accelerating the path to clinical applications and breakthrough therapies.

The robust and sophisticated informatics tools required for enabling PROTAC and TPD research must continuously evolve and support these five areas:

1. Data Integration and Management  Informatics platforms can facilitate the valuable integration and standardization of data from various sources, breaking down silos and creating a unified view of research data. For example, Signals Research Suite from Revvity Signals supports the management and analysis of data from in vitro and in vivo studies, enhancing collaboration and data accessibility.
2. Advanced Computational Modeling & Analytics   Advanced computational methods can model the complex interactions involved in TPD, such as ternary complex formation. These models and simulations help predict the physicochemical properties of degraders, assess the solubility and permeability of potential drug candidates, and optimize their design for better efficacy and selectivity. In addition, machine learning models, such as the Model-free Analysis of Protein Degradability (MAPD), are being used to predict the degradability of proteins based on intrinsic features. These tools help identify promising targets for TPD approaches, guiding drug development efforts.
3. Facilitating Multidisciplinary Collaboration  Informatics tools can provide platforms for interdisciplinary collaboration, integrating data from diverse sources and facilitating communication with real-time data sharing across different scientific domains. This enables a coordinated approach to TPD research that fosters a deeper culture of collaboration.
4. Enhancing Decision-Making  Comprehensive data analysis and visualization tools empower researchers to make data-driven decisions, accelerating the drug discovery process.
5. Streamlining Workflows Specialized informatics solutions offer TPD-specific workflows, addressing their unique aspects and improving efficiency throughout the development pipeline. Tools with user-friendly interfaces can further simplify the navigation of complex datasets and experimental designs.

By leveraging these capabilities, researchers can more effectively explore the complexity of TPD biology, establish new drug development paradigms tailored to these unique molecules, manage and accelerate drug discovery pipeline and ultimately work towards bringing life-changing therapies to patients faster. 

Enhancing PROTAC Research: Leveraging Revvity Signals’ Advanced Informatics Tools

The rapid development of PROTAC technology and TPD research presents significant opportunities in drug discovery. To fully harness the potential of these molecules, scientists need advanced informatics to manage the growing complexity.

Signals Research Suite from Revvity Signals is designed to address the unique challenges of TPD research by streamlining workflows, enhancing collaboration, and equipping scientists and decision-makers with critical insights to accelerate informed decisions. Our solution provides a comprehensive R&D workflow with cutting-edge data capture, processing, analytics, and collaboration capabilities.

Request a demo to explore Signals Research Suite's full capabilities. Then, take your research to the next level by contacting us. We'll help you find the right solution.