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Targeted Protein Degradation FAQs

What are the benefits of targeted protein degradation over traditional therapies?

Targeted protein degradation presents a revolutionary drug development strategy and has the potential to bring about a paradigm shift in modern healthcare. In the past, conventional pharmacological interventions have been severely restricted in terms of accessing protein targets of pathological significance. It is becoming increasingly evident that bifunctional protein degrader-based interventions possess the capability to access the part of the human proteome that was previously considered undruggable.

The methodology involves designing small molecules that can recruit the ubiquitin-proteasome system to make a target protein more pharmacologically vulnerable. The applications of this technology in drug discovery are numerous. As a result, targeted protein degradation-based therapeutics have generated immense interest within the scientific community, thereby, opening a new frontier in the field of medicine. Targeted protein degradation is a rapidly growing field that is expected to reach a market size of 10 billion USD by 2030. Also, many companies have sprung up which have focussed efforts on this domain. This strategy holds immense promise as it shows several advantages over traditional therapies such as 1) Target “undruggable” proteins, 2) Overcoming drug resistance in cancer, and 3) Eliminating enzymatic and non-enzymatic functions of kinases.

What are the challenges in the field of targeted protein degradation?

Targeted protein degradation is growing by leaps and bounds but faces some challenges which need immediate resolution. Some of these challenges include:

  1. Expanding the repertoire of E3 ligases
  2. Designing more potent degraders
  3. Identifying new targets which are amenable for degradation

In the recent past, we have seen rapid strides being taken in the field of targeted protein degradation. Burgeoning advances in pharmacology and medicinal chemistry have resulted in a goldmine of diverse and valuable data on biologically active degraders which can be exploited to increase their therapeutic benefit. Excelra is a data science and analytics company that has several years of experience in curating and structuring complex data sets. We have created proprietary databases which contain biological, chemical, and clinical data points that can be leveraged to solve these problems. Currently, only a handful of ligases are being exploited for degraders whereas the human genome encodes ~600 ligases. This along with information on physiological targets, expression, and localization, and disease association may help in expanding the repertoire of E3 ligases. Designing degraders with improved physicochemical and pharmacokinetic properties is also the need of the hour.

Excelra’s databases contain several thousands of degraders accompanied with their structure information, ligand details, linker information, and physico-chemical properties to aid in degrader design and development. Identification of appropriate targets that are amenable for targeted ablation is also crucial. We have information on ~1500 targets along with their ubiquitination sites, expression and localization and disease association.

What is the most promising degrader modality?

Although several types of degraders are available, PROTACs are the most versatile. They offer the advantages of a modular design wherein an appropriate target and ligase ligands can be brought in proximity with a linker. PROTACs offer the following advantages over traditional small molecule-based approaches:

  1. Catalytic mechanism of action resulting in potent and profound degradation of a target protein
  2. Fast and reversible chemical knockdown strategy
  3. Low dose requirement and enhanced target selectivity
  4. Can degrade fusion proteins, mutated proteins, etc which can be hugely beneficial in the clinical context
  5. Eliminating both enzymatic and non-enzymatic functions of kinases

Excelra’s databases contain several thousands of PROTACs along with information on individual components such as ligase ligand, target ligand, and linker. This information will be very valuable to drug discovery scientists.

What are the challenges in PROTAC design?

PROTACs show a lot of promise but several limitations are associated with this technology. Their properties lie outside the classical Lipinski’s rule of 5 and suffer from poor solubility, cell permeability, and pharmacokinetics.

However, there is a deluge of information regarding the availability of specific PROTAC components such as ligase ligands, target ligands, and linker scaffolds which can be combined to create degraders with more drug-like properties. Knowledge of physico-chemical properties, linker length, and flexibility can play a decisive role in designing hugely potent PROTACs. The biggest obstacle is the heterogeneity and uneven quality of data from various sources. Curation, harmonization, and integration of data from disparate sources is the critical need of the hour. Our data scientists extract and enhance data from various sources, providing pragmatic solutions to challenges in degrader drug discovery. Combining this with our domain expertise, we are well poised to address complex scientific questions to accelerate degrader development in a timely and cost-effective manner.

What are the databases Excelra is offering in TPD

Excelra offers a multitude of databases and services to resolve the pain points of TPD researchers mentioned earlier.

It is rare to find the right data all in one place. We have created two distinct databases viz. Degrader Intelligence Database and Degrader Discovery Database will be very beneficial to the TPD community.

  • Degrader Intelligence Database (DID) allows its users to capture a snapshot of the competitive landscape in the degrader space to understand the companies working in the area and the strategies leveraged by them. This also helps identify potential gaps in the space that could be opportunities for new entrants in the market.
    Degrader Discovery Database (D3) covers information on degraders and their properties which enable rational design of improved and efficacious drugs. Additionally, comprehensive information of ligase-substrate relationships along with the details of degradation associated will allow the initiation of new programs in this space.

These 2 databases have omnidirectional data which has been integrated from disparate and diverse data sources under one roof. Frequent updates allow users to remain current with the latest happenings in this space. These databases along with our extensive knowledge and relevant domain expertise enable us to offer custom services to the TPD community as well.

The Excelra Advantage

Excelra’s proprietary offerings in the TPD space are fuelled by our capabilities and 18+ years of experience in data collection, data curation and data annotation for our clients. Our substantial domain expertise in this area helps us in understanding the best approach for answering the problem statements of our clients.